VCV000007105.206 - ClinVar

NM_000492.3(CFTR):c.1521_1523del (p.Phe508del)

Germline

Practice guidelines

Practice guidelines. Learn more about how ClinVar calculates review status.

Pathogenic

for Cystic fibrosis

Classification is based on the practice guideline submission

Mar 2004 by American College of Medical Genetics and Genomics (ACMG)

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Cystic fibrosis

Classification is based on the expert panel submission

Mar 2017 by CFTR2

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Drug response

for ivacaftor / lumacaftor response - Efficacy

Classification is based on the expert panel submission

Mar 2021 by ClinPGx

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Drug response

for ivacaftor / tezacaftor response - Efficacy

Classification is based on the expert panel submission

Mar 2021 by ClinPGx

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000492.3(CFTR):c.[1521_1523delCTT;3080T>C]

Identifiers

NM_000492.3(CFTR):c.1521_1523del (p.Phe508del)

Variation ID: 7105 Accession: VCV000007105.206

Type and length

Deletion, 3 bp

Location

Cytogenetic: 7q31.2 7: 117559591-117559593 (GRCh38) [ NCBI UCSC ] 7: 117199645-117199647 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 22, 2013	May 3, 2026	Mar 3, 2004

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1520_1522del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000492.4:c.1520_1522delTCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000492.4:c.1521_1523del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Phe508del	inframe deletion
NM_000492.4:c.1521_1523delCTT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000492.3:c.1520_1522del
NM_000492.3:c.1520_1522delTCT
NM_000492.3:c.1521_1523delCTT
NC_000007.14:g.117559592_117559594del
NC_000007.13:g.117199646_117199648del
NG_016465.4:g.98809_98811del
LRG_663:g.98809_98811del
LRG_663t1:c.1521_1523del	LRG_663p1:p.Phe508del

... more HGVS ... less HGVS

Protein change

Other names

F508del
deltaF508
F508delF
DF508
Phe508del
DeltaF508
[delta]F508

Canonical SPDI

NC_000007.14:117559590:TCTT:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00399 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

Genetic Testing Registry (GTR): GTR000074114 Genetic Testing Registry (GTR): GTR000500233 Genetic Testing Registry (GTR): GTR000562170 Genetic Testing Registry (GTR): GTR000597400 OMIM: 602421.0001 dbSNP: rs113993960 ClinPGx Clinical Annotation: 981755820 ClinGen: CA118639 Genetic Testing Registry (GTR): GTR000028916 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	3900	6390
CFTR-AS1	-	-	-	GRCh38	-	628

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystic fibrosis	Pathogenic (51)	practice guideline	Mar 3, 2004	RCV000007523.116
Bronchiectasis with or without elevated sweat chloride 1, modifier of	risk factor (1)	no assertion criteria provided	May 17, 2015	RCV000007524.19
not provided	Pathogenic (20)	criteria provided, multiple submitters, no conflicts	Mar 1, 2026	RCV000058929.99
Hereditary pancreatitis	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 21, 2025	RCV000119038.22
Duodenal stenosis	Likely pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626692.10
Recurrent pancreatitis	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626693.10
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 6, 2025	RCV001004459.13
Obstructive azoospermia	Pathogenic (1)	criteria provided, single submitter	Aug 23, 2021	RCV001642198.10
ivacaftor / lumacaftor response - Efficacy	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV001787370.11
ivacaftor / tezacaftor response - Efficacy	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV001787371.11
CFTR-related disorder	Pathogenic (4)	criteria provided, single submitter	Jun 3, 2025	RCV001831519.17
Cystic fibrosis Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	Feb 1, 2022	RCV002243627.9
See cases	Pathogenic (1)	criteria provided, single submitter	May 3, 2019	RCV002251888.9
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 10, 2024	RCV002490332.11
Congenital bilateral aplasia of vas deferens from CFTR mutation	Pathogenic (1)	criteria provided, single submitter	-	RCV003227599.8
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 30, 2024	RCV003444054.5
Cystic fibrosis diagnostic test	Pathogenic (1)	criteria provided, single submitter	Oct 21, 2025	RCV005865162.1
click to load more conditions click to collapse

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 03, 2004) C Contributing to aggregate classification	practice guideline (Guideline for cystic fibrosis carrier screening)	Cystic fibrosis (Autosomal recessive inheritance)	American College of Medical Genetics and Genomics (ACMG) Study: The ACMG recommended carrier screening panel Accession: SCV000071392.3 First in ClinVar: Jun 04, 2013 Last updated: Jun 08, 2025	Publications: PubMed (1) PubMed: 11280952 pmc: 3110945 pmc: 3110945 Comment: show Converted during submission from pathogenic to Pathogenic. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Mar 17, 2017) N Not contributing to aggregate classification	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Cystic fibrosis	CFTR2 Study: CFTR2 Accession: SCV000071493.4 First in ClinVar: Oct 18, 2013 Last updated: Dec 26, 2017	Other databases https://cftr2.org https://cftr2.org Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

drug response Drug-variant association: Efficacy (Mar 24, 2021) N Not contributing to aggregate classification	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine)	ivacaftor / lumacaftor response - Efficacy Drug used for Cystic Fibrosis	ClinPGx Accession: SCV002031250.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (11) PubMed: 24973281‚ 25981758‚ 27298017‚ 27334259‚ 27805836‚ 27898234‚ 28325531‚ 28606620‚ 29126871‚ 29327948‚ 29451946 Other databases https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1447979749 https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166157525 Comment: show PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C93, HLA-B57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: yes Observation 1 Collection method: curation Allele origin: germline Affected status: yes

drug response Drug-variant association: Efficacy (Mar 24, 2021) N Not contributing to aggregate classification	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine)	ivacaftor / tezacaftor response - Efficacy Drug used for Cystic Fibrosis	ClinPGx Accession: SCV002031251.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (3) PubMed: 28930490‚ 29099333‚ 29099344 Other databases https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1449154729 https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166157525 Comment: show PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C93, HLA-B57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: yes Observation 1 Collection method: curation Allele origin: germline Affected status: yes

Pathogenic (Aug 26, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Genetic Services Laboratory, University of Chicago Accession: SCV000594089.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Jan 01, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Duodenal stenosis	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747395.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (Jan 01, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Recurrent pancreatitis	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747396.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (Jan 29, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	cystic fibrosis	CFTR-France Accession: SCV001169465.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Observation: 1 Collection method: curation Allele origin: germline Affected status: yes Observation 1 Collection method: curation Allele origin: germline Affected status: yes

Pathogenic (Oct 18, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Cystic fibrosis	Myriad Genetics, Inc. Accession: SCV001193905.2 First in ClinVar: Mar 25, 2020 Last updated: Jul 06, 2020	Publications: PubMed (2) PubMed: 15371902‚ 23974870 Comment: show NM_000492.3(CFTR):c.1521_1523delCTT(aka F508del) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870 and 15371902. Classification of NM_000492.3(CFTR):c.1521_1523delCTT(aka F508del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Oct 22, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary pancreatitis	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368335.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: show This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM3,PM4. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002053836.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Observation: 1 Collection method: clinical testing Allele origin: inherited Affected status: yes Observation 1 Collection method: clinical testing Allele origin: inherited Affected status: yes

Pathogenic (Feb 01, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary pancreatitis Cystic fibrosis	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512246.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: show ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong, PM3 strong, PM4 moderate, PP3 supporting (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Geographic origin: Brazil

Pathogenic (May 03, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	See cases	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523540.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: show ACMG classification criteria: PS3, PM2, PM4, PP1, PP4, PP5 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Abnormality of blood and blood-forming tissues (present) , Hepatosplenomegaly (present) , Fever (present) Geographic origin: Brazil

Pathogenic (May 12, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines)	Hereditary pancreatitis	Sema4, Sema4 Accession: SCV002529678.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The CFTR c.1521_1523delCTT (p.F508del) variant is the most common pathogenic variant in individuals with cystic fibrosis (PMID: 31523618, 27469177, 20301295). Functional studies have shown that … (more) The CFTR c.1521_1523delCTT (p.F508del) variant is the most common pathogenic variant in individuals with cystic fibrosis (PMID: 31523618, 27469177, 20301295). Functional studies have shown that this variant disrupts the protein function (PMID: 24727426). This variant was observed in 1598/129034 chromosomes in the Non-Finnish European population, with 1 homozygote, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 7105). Heterozygous carriers of the F508del variant are usually asymptomatic, however, may be at increased risk for developing pancreatitis, which can eventually lead to pancreatic cancer. Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (4) PubMed: 20301295‚ 24727426‚ 27469177‚ 31523618 Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Feb 01, 2013) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Arcensus Accession: SCV002564582.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Nov 05, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Cystic fibrosis	Mendelics Accession: SCV000886152.2 First in ClinVar: Jan 22, 2019 Last updated: Dec 11, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (Dec 08, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV002759371.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Pulmonary fibrosis (present)

Pathogenic (Nov 03, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009133.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided

Pathogenic (Nov 06, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital Accession: SCV004100881.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Publications: PubMed (1) PubMed: 2233932 Comment: show This is the most common CFTR pathogenic variant. The c.1521_1523delCTT variant results in an in-frame deletion of a single Phenylalanine residue at codon 508. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Zygosity: 1 Single Heterozygote

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Bronchiectasis with or without elevated sweat chloride 1 (Autosomal recessive inheritance)	Institute of Human Genetics, University Hospital of Duesseldorf Accession: SCV004171185.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Observation: 1 Collection method: not provided Allele origin: germline Affected status: yes Observation 1 Collection method: not provided Allele origin: germline Affected status: yes

Pathogenic (Nov 03, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000221179.6 First in ClinVar: Apr 08, 2015 Last updated: Apr 20, 2024	Publications: PubMed (5) PubMed: 11280952‚ 1381146‚ 23974870‚ 2570460‚ 9135274 Comment: show The p.Phe508del variant in CFTR (also known as ΔF508) is a deletion of a single amino acid at position 508 and is well-established as a pathogenic variant for autosomal recessive cystic fibrosis (Kerem 1989 PMID:2570460, Fuller 1992 PMID:1381146, Southern 1997 PMID:9135274, Grody 2001 PMID:11280952, Sosnay 2013 PMID:23974870). This is the most common pathogenic variant reported in CFTR and has been classified as Pathogenic by the ACMG practice guideline for cystic fibrosis carrier screening and the ClinGen-approved CFTR2 expert panel (ClinVar Variation ID 7105). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PS3, PM4_Supporting. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Oct 04, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Dubai Health Genomic Medicine Center, Dubai Health Accession: SCV002818128.2 First in ClinVar: Jan 07, 2023 Last updated: Dec 07, 2024	Comment: show PVS1, PM3_VeryStrong, PS3, PP4 (less) Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

pathogenic (Feb 21, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889288.5 First in ClinVar: Mar 13, 2019 Last updated: Jan 19, 2025	Publications: PubMed (162): PubMed: 10103316 10425036 10950058 10963013 11186891 11547256 11924117 12400067 1379413 14618962 15141088 15246977 15482777 15640323 15905293 16075239 16283887 16478680 17035430 17048214 1715308 17175965 17206681 1723032 18180206 18234567 18394117 18456578 18796364 19176844 19227414 19459534 19837664 19878303 19885835 19925455 1997384 20021716 20116881 20619026 20628052 20667826 20687163 20696241 20977904 21097845 21111762 21152102 21228398 21411740 21486785 21520337 21594800 21907281 21965669 21976147 21983488 22020151 22332135 22366207 22369017 22390181 22427236 22449949 22569626 22658665 22680785 22975760 22999299 23067305 23104983 23168765 23361109 23378603 23379606 23436935 23656801 23751316 23781395 2378364 23857699 23883480 23891399 23907436 23951356 23974870 24433235 24435787 24440181 24696795 2475911 25042876 25148434 25330774 25608981 25636364 25697321 2570460 25763566 25797027 26006199 26149808 26574590 26581802 26618866 26627831 26648081 26800689 26911355 26989879 27171515 27577878 27660821 27673710 28129809 28492530 28617084 28968805 29261177 29431110 29589582 29805046 30279124 30487145 30600599 30602999 30609409 31019283 31028937 31036917 31126253 31130284 31187952 31199594 31310009 31447099 31523618 31589614 31980526 32429104 32761997 33083013 33118704 33144682 33270637 33365035 33713579 34426522 38003474 38198345 7517267 7533604 7540133 7789957 8659542 8740923 8844211 8886242 9235853 9272738 9493456 9618063 Comment: show The CFTR c.1521_1523del (p.Phe508del) variant (also known as F508del and Delta F508) is the most common cystic fibrosis (CF) pathogenic variant that accounts for approximately 70% of alleles in affected patients (PMIDs: 23974870 (2013), 23857699 (2013), 8886242 (1996), 38003474 (2023)). It causes a severe phenotype due to deleterious effects on CFTR protein maturation and function (PMIDs: 23974870 (2013), 25148434 (2014), 26581802 (2016)). This variant, being so common in European CF cohorts, has a general population frequency of 0.016 (807/50740 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)). Based on the available information, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Jan 03, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000330918.5 First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025	Other databases http://www.cftr2.org/ http://www.cftr2.org/ http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR http://www.ncbi.nlm.nih.gov/site… http://www.ncbi.nlm.nih.gov/sites/GeneTests/review/gene/CFTR Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 210 Zygosity: 7 Homozygotes, 203 Single Heterozygotes Sex: mixed

Pathogenic (Nov 07, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Bronchiectasis with or without elevated sweat chloride 1 Hereditary pancreatitis Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili Accession: SCV004101389.2 First in ClinVar: Nov 11, 2023 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: Latin Geographic origin: Colombia

Pathogenic (Jun 12, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Revvity Omics, Revvity Accession: SCV002019253.4 First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 11, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Institute of Immunology and Genetics Kaiserslautern Accession: SCV006554430.1 First in ClinVar: Oct 12, 2025 Last updated: Oct 12, 2025	Comment: show ACMG Criteria: PS3, PS4, PM4, PP5_M; Variant was found in heterozygous state. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (IMAGENE.ME Variant Classification SOP 2022)	Cystic fibrosis	Imagene.me medical diagnostic laboratory, IMAGENE.ME SA Accession: SCV007329966.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	Comment: show Classified according to the IMAGENE.ME variant classification SOP based on the ACMG guidelines as Pathogenic (P). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jul 31, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Cystic fibrosis	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002048630.9 First in ClinVar: Jan 08, 2022 Last updated: Jan 24, 2026	Comment: show The CFTR c.1521_1523del; p.Phe508del (F508del) variant is the most common pathogenic CFTR variant that has been reported in Caucasians (Sosnay 2013, CFTR2 database). This variant is considered to cause cystic fibrosis when identified with another pathogenic variant on the opposite chromosome. REFERENCES CFTR2 database: http://cftr2.org/ Sosnay P et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45(10):1160-7. PMID: 23974870. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Oct 28, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511517.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Platform type: Sequencing Platform name: Illumina

Pathogenic (Dec 30, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Department of Genetics, Sultan Qaboos University Hospital Accession: SCV000891676.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Publications: PubMed (1) PubMed: 10782933 Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Geographic origin: Middle East

Pathogenic (Jul 30, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000329246.6 First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019	Comment: show The c.1521_1523delCTT pathogenic variant in the CFTR gene (also known as p.Phe508del or delta F508) is the most common variant identified in the CFTR gene, with up to 90% of individuals with cystic fibrosis (CF) having at least one copy of the c.1521_1523delCTT variant (Cai et al., 2011). The c.1521_1523delCTT variant results in an in-frame deletion of a single Phenylalanine residue at codon 508. Individuals who are homozygous for the c.1521_1523delCTT variant demonstrate the classic features of CF, whereas individuals compound heterozygous for the c.1521_1523delCTT variant and another CFTR variant may have a modified disease phenotype (Ong et al., 2017). Heterozygous carriers of the c.1521_1523delCTT variant are usually asymptomatic, however, may be at increased risk for developing a CFTR-related disorder, as an increased prevalence of single CFTR pathogenic variants has been observed among individuals with chronic pulmonary conditions, CAVD and pancreatitis (Cuppens et al., 2004; Bombieri et al., 2011). We interpret the c.1521_1523delCTT variant as a pathogenic variant. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Dec 12, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	not provided	Blueprint Genetics Accession: SCV000928113.1 First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 Comment: Patient analyzed with Primary Immunodeficiency Panel	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Baylor Genetics Accession: SCV001163504.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jun 04, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000883108.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Secondary finding: yes

Pathogenic (Sep 03, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Accession: SCV001244997.1 First in ClinVar: May 04, 2020 Last updated: May 04, 2020	Comment: show A heterozygous inframe deletion variant, NM_000492.3(CFTR):c.1521_1523del, has been identified in exon 11 of 27 in the CFTR gene. The variant is predicted to result in an inframe deletion of a single amino acid at position 508 of the protein, NP_000483.3(CFTR):p.(Phe508del). The phenylalanine at this position has very high conservation (UCSC, 100 vertebrates), and is located in the ABC transporter 1 functional domain. This variant is present in the gnomAD database at a frequency of 0.7% (2027 heterozygotes, 1 homozygote), and has been previously reported multiple times in individuals with cystic fibrosis, being the most common causative variant in the CFTR gene (ClinVar; Egan, ME. et al. (2016)). Analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. (less) Observation: 1 Collection method: clinical testing Allele origin: maternal Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: maternal Affected status: unknown Number of individuals with the variant: 2 Clinical Features: Esophageal atresia (present) , Tracheoesophageal fistula (present) , Choanal atresia (present) , Hypocalcemia (present) , Clinodactyly (present) , Short palpebral fissure (present) Test name: Whole Exome Sequencing Family history: yes Secondary finding: yes Platform type: next-gen sequencing

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: NSIGHT-NC NEXUS Accession: SCV001251533.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 Comment: carrier finding	Publications: PubMed (1) PubMed: 2233932 Bookshelf: NBK1250 Bookshelf: NBK1250 Comment: show The CFTR c.1521_1523delCTT (p.F508del) variant is the most common pathogenic CFTR variant (PMID: 20301428, 2233932). (less) Observation: 1 Collection method: research Allele origin: germline Affected status: no more Observation 1 Collection method: research Allele origin: germline Affected status: no Number of individuals with the variant: 2 Platform type: exome sequencing

Pathogenic (May 03, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV001251746.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: no Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: no

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	CENTOGENE GmbH and LLC - Guiding Precision Medicine Accession: SCV001424387.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Dec 30, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002061800.2 First in ClinVar: Jan 22, 2022 Last updated: Feb 05, 2022	Comment: show PS3, PP1, PM1, PM3, PM4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Mar 30, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502414.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (40) PubMed: 10103316‚ 10425036‚ 11924117‚ 15141088‚ 16283887‚ 16478680‚ 1715308‚ 17206681‚ 18180206‚ 18456578‚ 18796364‚ 19837664‚ 20628052‚ 21111762‚ 21228398‚ 21594800‚ 21983488‚ 22020151‚ 23379606‚ 23656801‚ 24435787‚ 24440181‚ 2475911‚ 25608981‚ 25763566‚ 25797027‚ 26149808‚ 26911355‚ 29261177‚ 30602999‚ 30609409‚ 31028937‚ 31036917‚ 31589614‚ 33083013‚ 33270637‚ 7540133‚ 8844211‚ 8886242‚ 9618063 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 5 Secondary finding: no Platform type: NGS

Pathogenic (Oct 11, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002507372.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis (Autosomal recessive inheritance)	Suma Genomics Accession: SCV002543782.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022	Observation: 1 Collection method: clinical testing Allele origin: inherited Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: inherited Affected status: yes Test name: Exome sequencing Platform type: Next Generation Sequencing

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Congenital bilateral aplasia of vas deferens from CFTR mutation (Autosomal recessive inheritance)	Lifecell International Pvt. Ltd Accession: SCV003925476.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Publications: PubMed (1) PubMed: 24958810 Comment: show A Heterozygous inframe indel variant c.1520_1522delTCT in Exon 11 of the CFTR gene that results in the amino acid substitution p.Phe508del was identified. The observed variant has a minor allele frequency of 0.00707/0.00800% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic. (Variant ID 7105). This variant has been previously reported for Indian patients with congenital absence of the vas deferens by Sharma H et al., 2014. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Zygosity: 1 Compound Heterozygote Ethnicity/Population group: Asian Geographic origin: India Platform type: Next-generation exome sequencing Platform name: NovaSeq 6000

Pathogenic (Feb 04, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Genetics and Molecular Pathology, SA Pathology Accession: SCV002761398.2 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2023	Publications: PubMed (4) PubMed: 1379413‚ 2570460‚ 7560099‚ 8092189 Comment: show This sequence change is an inframe deletion of 3 bp predicted to cause the deletion of phenylalanine at position 508 of the CFTR protein (p.Phe508del). The region deleted is highly conserved (100 vertebrates, UCSC) in a nonrepeat region, and is located in the ABC transporter domain. The variant is present in a large population cohort at a frequency of 0.7% (rs1297060838, 2,027/282,630 alleles, 1 homozygote in gnomAD v2.1). It is the most commonly reported pathongenic variant in CFTR, and is assigned a practice quideline pathogenic classification in ClinVar (ID: 7105). It has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in cystic fibrosis cases (PMID: 8092189, 1379413, 2570460). Additionally, a Cftr Phe508del/Phe508del mouse model lack CFTR in the apical membrane, were chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID: 7560099). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PM4_Supporting. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Mar 25, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004805438.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Pathogenic (Jan 07, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Baylor Genetics Accession: SCV001527339.4 First in ClinVar: Mar 22, 2021 Last updated: Jun 09, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Feb 01, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051724.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Observation: 1 Collection method: curation Allele origin: germline Affected status: no Observation 1 Collection method: curation Allele origin: germline Affected status: no

Pathogenic (Mar 30, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Bronchiectasis with or without elevated sweat chloride 1	Baylor Genetics Accession: SCV004211619.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Jan 11, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197698.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jan 24, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397656.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (3) PubMed: 15371902‚ 23974870‚ 2475911 Comment: show This sequence variant is an in-frame deletion of 3 nucleotides spanning positions 1521 through 1523 of the coding sequence of the CFTR gene that removes Phe508 of the CF transmembrane conductance regulator protein. This is a previously reported (ClinVar 7105), well characterized variant (PMID: 15371902) that is the most common cystic fibrosis-associated variant in the general population (PMID: 23974870). The variant is also known as deltaF508 and similar identifiers in the literature and public databases. This variant is present in 2976 of 403344 alleles (0.7378%) in the gnomAD population dataset. Experimental evidence shows that function of the variant protein is significantly inhibited (PMID: 2475911). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM4, PS3, PS4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Platform type: Next-gen sequencing

Pathogenic (Sep 02, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cystic fibrosis	Ambry Genetics Accession: SCV000741228.6 First in ClinVar: Apr 15, 2018 Last updated: Jan 13, 2025	Publications: PubMed (3) PubMed: 11733566‚ 23974870‚ 26976279 Comment: show The p.F508del pathogenic mutation (also known as deltaF508 and c.1521_1523delCTT) is located in coding exon 11 of the CFTR gene. This pathogenic mutation results from an in-frame CTT deletion at nucleotide positions 1521 to 1523. This results in the in-frame deletion of a phenylalanine at codon 508. This mutation is associated with elevated sweat chloride levels, lung disease, pancreatic insufficiency, and Pseudomonas infection; in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Disease expression is variable, even among individuals homozygous for p.F508del (Bronsveld I et al. J. Clin. Invest., 2001 Dec;108:1705-15). This mutation accounts for approximately 70% of cystic fibrosis chromosomes worldwide; it is a class II mutation which results in a misfolded CFTR protein that is subsequently degraded (Esposito S et al. Mol Cell Pediatr, 2016 Dec;3:13). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 04, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004242533.3 First in ClinVar: Feb 14, 2024 Last updated: Mar 11, 2025	Publications: PubMed (5) PubMed: 20667826‚ 21486785‚ 28617084‚ 36404349‚ 7789957 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 17, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (Classification criteria August 2017)	Cystic fibrosis (Autosomal recessive inheritance)	Institute of Human Genetics Munich, TUM University Hospital Accession: SCV001149705.2 First in ClinVar: Feb 03, 2020 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: inherited Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: inherited Affected status: yes Zygosity: 1 Homozygote Sex: male Tissue: blood

Pathogenic (Jul 22, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Genome-Nilou Lab Accession: SCV001810348.2 First in ClinVar: Sep 08, 2021 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Sex: mixed

Pathogenic (Feb 14, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Dasa Accession: SCV002097285.2 First in ClinVar: Feb 20, 2022 Last updated: Apr 13, 2025	Publications: PubMed (6) PubMed: 27738188‚ 29614238‚ 29668297‚ 29944384‚ 30030066‚ 30089726 Comment: show Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 30030066; 27738188) - PS3. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 7105; PMID: 30089726; 29614238; 29668297; 29944384) - PS4. The p.(Phe508del) was detected in trans with a pathogenic variant (PMID: 30089726; 29614238) - PM3_very strong. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4 and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 5 Sex: mixed Geographic origin: Brazil

Pathogenic (Aug 30, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	MGZ Medical Genetics Center Accession: SCV002579737.2 First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025 Comment: ACMG criteria applied: PM3_VSTR, PS3, PS4, PM4, PP4	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 30 Sex: female

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Suma Genomics Accession: SCV004037030.2 First in ClinVar: Sep 30, 2023 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Zygosity: 1 Homozygote Age: 0-9 years Sex: female

Pathogenic (Feb 15, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Bronchiectasis with or without elevated sweat chloride 1 (Autosomal dominant inheritance)	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004698102.2 First in ClinVar: Mar 10, 2024 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Elevated sweat chloride (present) , Bronchiectasis (present) Sex: female

Pathogenic (Feb 16, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Laboratory of Genetics, Children's Clinical University Hospital Latvia Accession: SCV006109277.1 First in ClinVar: Jul 05, 2025 Last updated: Jul 05, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

pathogenic (Aug 21, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary pancreatitis (Autosomal dominant inheritance)	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV006554384.1 First in ClinVar: Oct 12, 2025 Last updated: Oct 12, 2025	Comment: show Criteria applied: PM3_VSTR,PS3,PM4 (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Pancreatitis (present) Sex: female

Pathogenic (Apr 14, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV006555683.1 First in ClinVar: Oct 18, 2025 Last updated: Oct 18, 2025	Comment: show The CFTR c.1521_1523del (p.Phe508del) variant, also known as delta508, has been reported in the homozygous or trans heterozygous state in many individuals affected with cystic fibrosis and is the most commonly reported pathogenic variant (cftr2.org; Sosnay PR et al., PMID: 23974870). The ACMG practice guidelines classify this variant as pathogenic (ClinVar Variation ID: 7105). Additionally, a Cftr Phe508del homozygous mouse model recapitulates human disease (Zeiher BG et al., PMID: 7560099). The highest population minor allele frequency in the population database genome aggregation database (v.4.1.0) is 1.5% in the European (non-Finnish) population which is consistent with the carrier rate of cystic fibrosis. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Oct 21, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis diagnostic test	NHS Central & South Genomic Laboratory Hub Accession: SCV006561073.1 First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

pathogenic (Sep 01, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002072562.5 First in ClinVar: Feb 05, 2022 Last updated: Oct 25, 2025	Comment: show Criteria applied: PM3_VSTR,PS3,PM4 (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Elevated sweat chloride (present) , Elevated circulating trypsinogen concentration (present) Sex: male

Pathogenic (Feb 02, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	3billion Accession: SCV003841941.4 First in ClinVar: Mar 18, 2023 Last updated: Oct 25, 2025	Publications: PubMed (2) PubMed: 2475911‚ 26857764 Comment: show The variant is observed in the gnomAD v4.1.0 dataset (total allele frequency: 1.193%). Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26857764). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000007105 /PMID: 2475911 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Method: genome sequencing

Pathogenic (Nov 20, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713417.5 First in ClinVar: Jun 15, 2021 Last updated: Jan 11, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 434

Pathogenic (Mar 26, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Variantyx Assertion Criteria 2022)	Cystic fibrosis	Variantyx, Inc. Accession: SCV007448776.1 First in ClinVar: Feb 15, 2026 Last updated: Feb 15, 2026	Comment: show This is an inframe substitution variant in the CFTR gene (OMIM: 602421). Pathogenic variants in this gene have been associated with autosomal recessive cystic fibrosis. This variant has been identified in the homozygous or compound heterozygous state in many unrelated affected individuals (PMID: 23974870). Functional studies have shown that this variant alters CFTR protein function (PMID: 21594800, 20628052, 25763566, 21152102, 26149808) (PS3). Other reputable laboratories have reported this variant as pathogenic or likely pathogenic, and this classification has been validated by an expert panel in ClinVar (PP5). This variant has a 1.4943% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal recessive cystic fibrosis. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Feb 04, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cystic fibrosis	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000074347.16 First in ClinVar: Jul 03, 2013 Last updated: Feb 23, 2026	Publications: PubMed (4) PubMed: 15371902‚ 23974870‚ 2475911‚ 28492532 Comment: show This variant, c.1521_1523delCTT, results in the deletion of 1 amino acid of the CFTR protein (p.Phe508del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs199826652, gnomAD 1.2%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with cystic fibrosis and is the most common cause of the condition (PMID: 2475911, 15371902, 23974870). It has also been observed to segregate with disease in related individuals. This variant is also known as deltaF508. ClinVar contains an entry for this variant (Variation ID: 7105). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CFTR function (PMID: 2475911, 23974870). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jun 03, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	CFTR-related disorders	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046363.3 First in ClinVar: Oct 21, 2023 Last updated: Mar 28, 2026	Publications: PubMed (18) PubMed: 1370875‚ 1377276‚ 1384321‚ 16554808‚ 1673094‚ 17873061‚ 1997384‚ 20301428‚ 21658649‚ 22081250‚ 24624459‚ 2475911‚ 27189798‚ 27738188‚ 30030066‚ 31882447‚ 35650428‚ 36498475 Comment: show This variant is also known as deltaF508 and has been previously reported as the most common pathogenic variant in the CFTR gene (PMID: 35650428, 36498475). Functional studies have demonstrated that this variant disrupts the normal function of the protein (PMID: 2475911, 17873061). It is present in the gnomAD v4 population database at a frequency of 1.2% (19237/1612320), including 58 homozygotes. Based on the available evidence, the c.1521_1523del (p.Phe508del) variant is classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jan 06, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. (Autosomal recessive inheritance)	First Genomix Gene Laboratory, Genetic Diagnostics Department Accession: SCV007580311.1 First in ClinVar: May 03, 2026 Last updated: May 03, 2026	Comment: show As part of Carrier Screening testing performed at First Genomix, this variant was identified in a heterozygous state in a patient who is not affected with this condition. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1

Pathogenic (Mar 30, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000538017.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Comment: show The c.1521_1523delCTT (p.Phe508del), also known as Î”F508, is an in-frame deletion in the CFTR gene. This variant is the most common CF-causing mutation, accounting for an estimated 72% of mutant alleles in people of European ancestry (Watson et al., 2004). This p.Phe508del variant is classified as a class II mutation that blocks the processing of the CFTR protein (Welsh et al., 2001). This variant has been reported at low frequencies (1.0%) in 1000 Genomes and ExAc population databases, but has not been reported in the Exome Sequencing Project database (ESP). The CFTR2 database has 32,833 patients that have this mutation, which they classify as CF-causing (http://www.cftr2.org/mutation.php?view=general&mutation_id=1). Therefore, this collective evidence supports the classification of the c.1521_1523delCTT (p.Phe508del) as a recessive pathogenic variant for Cystic fibrosis. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Oct 21, 2013) N Not contributing to aggregate classification	criteria provided, single submitter (HA_assertions_20150911)	Cystic fibrosis	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-HudsonAlpha Accession: SCV000584079.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Observation: 35 Observation 1 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 2 Collection method: research Allele origin: paternal Affected status: unknown Number of individuals with the variant: 1 Observation 3 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 4 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 5 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 6 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 7 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 8 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 9 Collection method: research Allele origin: paternal Affected status: unknown Number of individuals with the variant: 1 Observation 10 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 11 Collection method: research Allele origin: paternal Affected status: unknown Number of individuals with the variant: 1 Observation 12 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 13 Collection method: research Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1 Observation 14 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 15 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 16 Collection method: research Allele origin: paternal Affected status: unknown Number of individuals with the variant: 1 Observation 17 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 18 Collection method: research Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1 Observation 19 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 20 Collection method: research Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1 Observation 21 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 22 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 23 Collection method: research Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1 Observation 24 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 25 Collection method: research Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1 Observation 26 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 27 Collection method: research Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1 Observation 28 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 29 Collection method: research Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1 Observation 30 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 31 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 32 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 33 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 34 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Observation 35 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1

Pathogenic (Jan 15, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV000864219.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jul 29, 2014) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450105.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 27

Pathogenic (Aug 23, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Obstructive azoospermia	Institute of Reproductive Genetics, University of Münster Accession: SCV001860325.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 10

Pathogenic (Feb 28, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary pancreatitis	Human Genetics Bochum, Ruhr University Bochum Accession: SCV004042777.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: show ACMG criteria used to clasify this variant:PS4, PM3_STR, PM4, PS3_SUP, PP1 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Mar 01, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary pancreatitis (Autosomal dominant inheritance)	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004176446.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: show The inframe deletion c.1521_1523del (p.Phe508del) variant in the CFTR gene has been reported previously in multiple individuals in homozygous/compound heterozygous state affected with Cystic fibrosis related disorders (Sosnay et al., 2013; Terlizzi et al., 2021). The p.Phe508del variant is the most frequent deletion that occurs in ~85% of Cystic fibrosis patients worldwide and is described to affect CFTR (class II) protein processing (Awatade et al. 2019). Experimental studies have shown that this variant affects CFTR function (Zeiher et al. 1995). The p.Phe508del variant is reported with an allele frequency of 0.7% in the gnomAD exomes database and is novel (not in any individuals) in the 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This p.Phe508del causes the deletion of the amino acid Phenylalanine at position 508. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Abnormality of the pancreas (present)

Pathogenic (Jun 22, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004101520.3 First in ClinVar: Nov 11, 2023 Last updated: Jan 04, 2025	Comment: show The observed inframe deletion c.1521_1523del p.Phe508del variant in the CFTR gene has been reported previously in multiple individuals in homozygous/ compound heterozygous state affected with Cystic fibrosis. Experimental studies have shown that this variant affects CFTR function Sosnay et al., 2013; Terlizzi et al., 2021. The p.Phe508del variant is the most frequent deletion that occurs in ~85% of Cystic fibrosis patients worldwide and is described to affect CFTR class II protein processing. The p.Phe508del variant is reported with an allele frequency of 0.7% in the gnomAD exomes database and is novel not in any individuals in the 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This p.Phe508del causes the deletion of the amino acid Phenylalanine at position 508. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Abnormal respiratory system physiology (present) Comment on clinical features: Clinical symptoms: Hyponatremia, hypokalemia, hypochloremia, failure to thrive, recurrent episodes of dehydration, AKI Clinical suspicion: Cystic fibrosis, Bartter syndrome

Pathogenic (Jun 10, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary pancreatitis Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Fulgent Genetics, Fulgent Genetics Accession: SCV002810876.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 05, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Molecular Genetics, Royal Melbourne Hospital Accession: SCV002503785.3 First in ClinVar: Apr 23, 2022 Last updated: Mar 29, 2025	Publications: PubMed (5) PubMed: 1379413‚ 2570460‚ 25910067‚ 7560099‚ 8092189 Comment: show This sequence change is an inframe deletion of 3 bp predicted to cause the deletion of phenylalanine at position 508 of the CFTR protein, p.(Phe508del). The region deleted is highly conserved (100 vertebrates, Multiz Alignments) in a nonrepeat region, and is located in the ABC transporter domain. The highest population minor allele frequency in the population database gnomAD v4.1 is 1.5% (17,610/1,178,514 alleles, 49 homozygotes) in the European (non-Finnish) population. It is the most commonly reported pathogenic variant in CFTR and is assigned a practice guideline pathogenic classification (ClinVar ID: 7105). It has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in cystic fibrosis cases and segregates with disease in multiple families (PMID: 8092189, 1379413, 2570460, 25910067). Additionally, a Cftr Phe508del/Phe508del mouse model lacks CFTR in the apical membrane, was chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID: 7560099). Based on the classification scheme RMH ACMG Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Moderate, PM4_Supporting, BS1. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Oct 18, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis (Autosomal recessive inheritance)	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV001161676.3 First in ClinVar: Mar 16, 2020 Last updated: Aug 03, 2025	Comment: show A homozygous 3 base pair deletion in exon 11 of the CFTR gene that results in the in-frame deletion of Phenylalanine was detected. The observed variant c.1521_1523del (p.Phe508del) has a minor allele frequency of 0.4% and 0.68% in the 1000 Genomes and ExAC databases respectively. The observed variation has previously been identified in patients affected with cystic fibrosis and it lies in the ABC transporter domain of the CFTR protein (Riordan et al 1989). The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Pallor (present) , Ascites (present) Comment on clinical features: INR level was deranged and serum albumin level was low. Zygosity: 1 Homozygote Age: 0-9 years Sex: female Ethnicity/Population group: Indian Hindu Geographic origin: India Comment on evidence: "loss_of_function_variant" was previously submitted as the functional consequence for NM_000492.4:c.1521_1523del, but without providing the result of a functional assay. Platform type: Next-generation sequencing Platform name: Illumina sequencing platform Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.

Pathogenic (Nov 07, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Department of Human Genetics, Hannover Medical School Accession: SCV007540636.1 First in ClinVar: Apr 18, 2026 Last updated: Apr 18, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Mar 01, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246813.37 First in ClinVar: May 12, 2020 Last updated: Apr 25, 2026	Comment: show CFTR: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PM4:Supporting (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 99

Pathogenic (Nov 02, 2023) N Not contributing to aggregate classification	no assertion criteria provided	Cystic fibrosis	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004101106.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

risk factor (May 17, 2015) N Not contributing to aggregate classification	no assertion criteria provided	BRONCHIECTASIS WITH OR WITHOUT ELEVATED SWEAT CHLORIDE 1, MODIFIER OF	OMIM Accession: SCV000053487.10 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (24) PubMed: 1370875‚ 1377276‚ 1380673‚ 1384321‚ 1536179‚ 15367919‚ 1673094‚ 1756602‚ 18507830‚ 1997384‚ 20595578‚ 20705837‚ 2210767‚ 2220803‚ 2236053‚ 22981120‚ 2300168‚ 24958810‚ 2570460‚ 25981758‚ 26618866‚ 7509564‚ 7537148‚ 9439669 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In individuals with cystic fibrosis (CF; 219700), Kerem et al. (1989) identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to … (more) In individuals with cystic fibrosis (CF; 219700), Kerem et al. (1989) identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to deletion of phenylalanine at codon 508 (delta-F508). The exon in which the delta-F508 mutation occurs has been corrected to exon 11; see, e.g., Sharma et al. (2014). The European Working Group on CF Genetics (1990) published information on the distribution of the delta-F508 mutation in Europe. The data, illustrated with a useful map, indicated a striking cline across Europe from low values of 30% in the southeast (in Turkey) to high values in the northwest (e.g., 88% in Denmark). The group suggested that the spread of the CF gene might have accompanied the migrations of early farmers starting from the Middle East and slowly progressing toward the northwest of Europe. The diffusion of the gene may have been favored by the selective advantage conferred by the gene. Strong association with the so-called haplotype B was demonstrated. The possibility of 'hitchhiking,' i.e., the influence of neighboring genes was discussed. Rozen et al. (1990) found the delta-F508 mutation in 71% of CF chromosomes from urban Quebec province French Canadian families, 55% of those from Saguenay-Lac-Saint-Jean region families and in 70% of those from Louisiana Acadian families. De Braekeleer (1991) estimated that the frequency at birth of cystic fibrosis is 1/926 in the Saguenay-Lac-Saint-Jean region, giving a carrier rate of 1/15. For the same region, Daigneault et al. (1991) reported a prevalence of CF at birth of 1/902 liveborns, and a carrier rate of 1/15. Rozen et al. (1992) found that the delta-F508 mutation was present in 58% of Saguenay-Lac-Saint-Jean CF families, with the G-to-T donor splice site mutation after codon 621 being found in 23%, and the A455E mutation (602421.0007) in 8%. The latter 2 mutations were not found in urban Quebec families. This provided further evidence of the role of founder effect. Among 293 patients, Kerem et al. (1990) found that those who were homozygous for the F508 deletion had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency. Pancreatic insufficiency was present in 99% of the homozygous patients, 72% of those heterozygous for the deletion, and only 36% of patients with other mutations. Wauters et al. (1991) studied the frequency of the delta-F508 mutation among Belgian patients with CF. The mutation was present in 80% of CF chromosomes from 36 unrelated families. Ninety-three percent of the CF chromosomes carrying the delta-F508 mutation also carried haplotype B in this population. Gille et al. (1991) described a strategy for efficient heterozygote screening for the delta-F508 mutation. They showed that PCR could detect a heterozygote in a pool of up to 49 unrelated DNA samples. Lerer et al. (1992) reported that the delta-F508 mutation accounts for 33.8% of Jewish CF alleles. The Basque population is thought to be one of the oldest in Europe, having been established in western Europe during the late Paleolithic Age. Euskera, the Basque language, is thought to be pre-Indo-European, originating from the first settlers of Europe. The variable distribution of the delF508 mutation in Europe, with higher frequencies in northern Europe and lower frequencies in southern Europe, has been attributed to a spread of the mutation by early farmers migrating from the Middle East during the Neolithic period. However, a very high frequency of this mutation was found in the Basque Provinces, where the incidence of CF is approximately 1 in 4,500. In a study of 45 CF families from the Basque Provinces, Casals et al. (1992) found that the frequency of the delF508 mutation was 87% in the chromosomes of individuals of pure Basque extraction and 58% in those of mixed Basque origin. Casals et al. (1992) proposed that the delF508 mutation was present in Europe more than 10,000 years ago, preceding the agricultural migrations which diluted the mutation rather than introducing it. Ballabio et al. (1990) described an allele-specific amplification method for diagnosing the phenylalanine-508 deletion. Among Pueblo and Navajo Native Americans of the U.S. Southwest, Grebe et al. (1992) found no instance of the delF508 mutation in 12 affected individuals. Clinically, 6 of the affected individuals had growth deficiency and 5 (all from the Zuni Pueblo) had a severe CF phenotype. Four of the 6 Zunis with CF were also microcephalic, a finding not previously noted in CF patients. In an analysis of 640 Spanish cystic fibrosis families, Casals et al. (1997) found that 75 mutations accounted for 90.2% of CF chromosomes - an extraordinarily high heterozygosity. The frequency of the delta-F508 mutation was 53.2%. The next most frequent mutation was gly542 to ter (602421.0009) with a frequency of 8.43%. Using 3 intragenic microsatellites of the CFTR gene located in introns, Russo et al. (1995) evaluated linkage disequilibrium between each marker and various CF mutations on a total of 377 CF and 358 normal chromosomes from Italian subjects. Results were considered consistent with the hypothesis that all del508 chromosomes derived from a single mutational event. The same hypothesis was valid for 3 other mutations which might have originated more recently than del508. Grebe et al. (1994) performed molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States. Only 46% (59 of 129) carried mutation F508del (frequency in the general population 67.1%). In 69 Italian patients with CF due to homozygosity for the delF508 mutation, De Rose et al. (2005) found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients. In a 62-year-old woman with idiopathic bronchiectasis (BESC1; 211400) and elevated sweat chloride but normal nasal potential difference, who carried a heterozygous F508del CFTR mutation, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The patient had a forced expiratory volume in 1 second (FEV1) that was 89% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C (602963) and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology. Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 32 heterozygotes and no homozygotes for the phe508del mutation in the CFTR gene, for a frequency of 0.022, or 1 in 45.5. This frequency is lower than that for the general population for this mutation, which is 1 in 30. Pankow et al. (2015) reported the first comprehensive analysis of the CFTR and delta-F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, they identified 638 individual high-confidence CFTR interactors and discovered a delta-F508 deletion-specific interactome, which is extensively remodeled upon rescue. Detailed analysis of the interactome remodeling identified key novel interactors, whose loss promote delta-F508i CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. The results of Pankow et al. (2015) demonstrated that global remodeling of delta-F508 CFTR interactions is crucial for rescue, and provided comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508. Clinical Trials Wainwright et al. (2015) conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator. A total of 1,108 patients 12 years of age or older who were homozygous for the Phe508del CFTR mutation were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary endpoint was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. In both studies, there were significant improvements in the primary endpoint. The difference between active and placebo with respect to mean absolute improvement in the percentage FEV1 ranged from 2.6 to 4.0 percentage points (p less than 0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (p less than 0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the treated groups than in the placebo group. In addition, the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the treated groups. The incidence of adverse events was similar in the treated and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. Wainwright et al. (2015) concluded that the combination of a CFTR corrector and potentiator, designed to address the underlying cause of cystic fibrosis by targeting CFTR, can benefit the 45% of patients who are homozygous for the Phe508del mutation. (less)

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001553614.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: show The CFTR p.F508del variant is the most common variant known to cause cystic fibrosis (CF); this variant acounts for ~70% of CFTR variants and is present in approximately 85% of CF patients worldwide (Maiuri_2015_PMID:26046070). The variant was identified in dbSNP (ID: rs113993960) and ClinVar (classified as pathogenic by the American College of Medical Genetics and Genomics, Laboratory for Molecular Medicine and 20+ other laboratories). The variant was identified in control databases in 2027 of 282630 chromosomes (1 homozygous) at a frequency of 0.007172 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1598 of 129034 chromosomes (freq: 0.01238), Other in 49 of 7214 chromosomes (freq: 0.006792), Ashkenazi Jewish in 58 of 10368 chromosomes (freq: 0.005594), Latino in 135 of 35426 chromosomes (freq: 0.003811), African in 65 of 24958 chromosomes (freq: 0.002604), European (Finnish) in 61 of 25074 chromosomes (freq: 0.002433) and South Asian in 61 of 30608 chromosomes (freq: 0.001993), but was not observed in the East Asian population. This variant is an in-frame deletion resulting in the removal of a phenylalanine (F) residue at codon 508; the deletion of p.F508 results in a misfolded mutant protein that is prematurely degraded before it reaches the plasma membrane (Maiuri_2015_PMID:26046070). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV001929598.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV002035293.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Mar 17, 2017) N Not contributing to aggregate classification	no assertion criteria provided	CFTR-related disorders	Natera, Inc. Accession: SCV002080609.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Oct 11, 2019) N Not contributing to aggregate classification	no assertion criteria provided	CFTR-related disorders	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002507456.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Cystic fibrosis	Genomics And Bioinformatics Analysis Resource, Columbia University Accession: SCV004024086.1 First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 Comment: Homozygous	Observation: 1 Collection method: research Allele origin: unknown Affected status: yes Observation 1 Collection method: research Allele origin: unknown Affected status: yes

Pathogenic (May 17, 2015) N Not contributing to aggregate classification	no assertion criteria provided	CYSTIC FIBROSIS	OMIM Accession: SCV000027724.10 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (24) PubMed: 1370875‚ 1377276‚ 1380673‚ 1384321‚ 1536179‚ 15367919‚ 1673094‚ 1756602‚ 18507830‚ 1997384‚ 20595578‚ 20705837‚ 2210767‚ 2220803‚ 2236053‚ 22981120‚ 2300168‚ 24958810‚ 2570460‚ 25981758‚ 26618866‚ 7509564‚ 7537148‚ 9439669 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In individuals with cystic fibrosis (CF; 219700), Kerem et al. (1989) identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to … (more) In individuals with cystic fibrosis (CF; 219700), Kerem et al. (1989) identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to deletion of phenylalanine at codon 508 (delta-F508). The exon in which the delta-F508 mutation occurs has been corrected to exon 11; see, e.g., Sharma et al. (2014). The European Working Group on CF Genetics (1990) published information on the distribution of the delta-F508 mutation in Europe. The data, illustrated with a useful map, indicated a striking cline across Europe from low values of 30% in the southeast (in Turkey) to high values in the northwest (e.g., 88% in Denmark). The group suggested that the spread of the CF gene might have accompanied the migrations of early farmers starting from the Middle East and slowly progressing toward the northwest of Europe. The diffusion of the gene may have been favored by the selective advantage conferred by the gene. Strong association with the so-called haplotype B was demonstrated. The possibility of 'hitchhiking,' i.e., the influence of neighboring genes was discussed. Rozen et al. (1990) found the delta-F508 mutation in 71% of CF chromosomes from urban Quebec province French Canadian families, 55% of those from Saguenay-Lac-Saint-Jean region families and in 70% of those from Louisiana Acadian families. De Braekeleer (1991) estimated that the frequency at birth of cystic fibrosis is 1/926 in the Saguenay-Lac-Saint-Jean region, giving a carrier rate of 1/15. For the same region, Daigneault et al. (1991) reported a prevalence of CF at birth of 1/902 liveborns, and a carrier rate of 1/15. Rozen et al. (1992) found that the delta-F508 mutation was present in 58% of Saguenay-Lac-Saint-Jean CF families, with the G-to-T donor splice site mutation after codon 621 being found in 23%, and the A455E mutation (602421.0007) in 8%. The latter 2 mutations were not found in urban Quebec families. This provided further evidence of the role of founder effect. Among 293 patients, Kerem et al. (1990) found that those who were homozygous for the F508 deletion had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency. Pancreatic insufficiency was present in 99% of the homozygous patients, 72% of those heterozygous for the deletion, and only 36% of patients with other mutations. Wauters et al. (1991) studied the frequency of the delta-F508 mutation among Belgian patients with CF. The mutation was present in 80% of CF chromosomes from 36 unrelated families. Ninety-three percent of the CF chromosomes carrying the delta-F508 mutation also carried haplotype B in this population. Gille et al. (1991) described a strategy for efficient heterozygote screening for the delta-F508 mutation. They showed that PCR could detect a heterozygote in a pool of up to 49 unrelated DNA samples. Lerer et al. (1992) reported that the delta-F508 mutation accounts for 33.8% of Jewish CF alleles. The Basque population is thought to be one of the oldest in Europe, having been established in western Europe during the late Paleolithic Age. Euskera, the Basque language, is thought to be pre-Indo-European, originating from the first settlers of Europe. The variable distribution of the delF508 mutation in Europe, with higher frequencies in northern Europe and lower frequencies in southern Europe, has been attributed to a spread of the mutation by early farmers migrating from the Middle East during the Neolithic period. However, a very high frequency of this mutation was found in the Basque Provinces, where the incidence of CF is approximately 1 in 4,500. In a study of 45 CF families from the Basque Provinces, Casals et al. (1992) found that the frequency of the delF508 mutation was 87% in the chromosomes of individuals of pure Basque extraction and 58% in those of mixed Basque origin. Casals et al. (1992) proposed that the delF508 mutation was present in Europe more than 10,000 years ago, preceding the agricultural migrations which diluted the mutation rather than introducing it. Ballabio et al. (1990) described an allele-specific amplification method for diagnosing the phenylalanine-508 deletion. Among Pueblo and Navajo Native Americans of the U.S. Southwest, Grebe et al. (1992) found no instance of the delF508 mutation in 12 affected individuals. Clinically, 6 of the affected individuals had growth deficiency and 5 (all from the Zuni Pueblo) had a severe CF phenotype. Four of the 6 Zunis with CF were also microcephalic, a finding not previously noted in CF patients. In an analysis of 640 Spanish cystic fibrosis families, Casals et al. (1997) found that 75 mutations accounted for 90.2% of CF chromosomes - an extraordinarily high heterozygosity. The frequency of the delta-F508 mutation was 53.2%. The next most frequent mutation was gly542 to ter (602421.0009) with a frequency of 8.43%. Using 3 intragenic microsatellites of the CFTR gene located in introns, Russo et al. (1995) evaluated linkage disequilibrium between each marker and various CF mutations on a total of 377 CF and 358 normal chromosomes from Italian subjects. Results were considered consistent with the hypothesis that all del508 chromosomes derived from a single mutational event. The same hypothesis was valid for 3 other mutations which might have originated more recently than del508. Grebe et al. (1994) performed molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States. Only 46% (59 of 129) carried mutation F508del (frequency in the general population 67.1%). In 69 Italian patients with CF due to homozygosity for the delF508 mutation, De Rose et al. (2005) found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients. In a 62-year-old woman with idiopathic bronchiectasis (BESC1; 211400) and elevated sweat chloride but normal nasal potential difference, who carried a heterozygous F508del CFTR mutation, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The patient had a forced expiratory volume in 1 second (FEV1) that was 89% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C (602963) and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology. Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 32 heterozygotes and no homozygotes for the phe508del mutation in the CFTR gene, for a frequency of 0.022, or 1 in 45.5. This frequency is lower than that for the general population for this mutation, which is 1 in 30. Pankow et al. (2015) reported the first comprehensive analysis of the CFTR and delta-F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, they identified 638 individual high-confidence CFTR interactors and discovered a delta-F508 deletion-specific interactome, which is extensively remodeled upon rescue. Detailed analysis of the interactome remodeling identified key novel interactors, whose loss promote delta-F508i CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. The results of Pankow et al. (2015) demonstrated that global remodeling of delta-F508 CFTR interactions is crucial for rescue, and provided comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508. Clinical Trials Wainwright et al. (2015) conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator. A total of 1,108 patients 12 years of age or older who were homozygous for the Phe508del CFTR mutation were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary endpoint was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. In both studies, there were significant improvements in the primary endpoint. The difference between active and placebo with respect to mean absolute improvement in the percentage FEV1 ranged from 2.6 to 4.0 percentage points (p less than 0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (p less than 0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the treated groups than in the placebo group. In addition, the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the treated groups. The incidence of adverse events was similar in the treated and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. Wainwright et al. (2015) concluded that the combination of a CFTR corrector and potentiator, designed to address the underlying cause of cystic fibrosis by targeting CFTR, can benefit the 45% of patients who are homozygous for the Phe508del mutation. (less)

Pathogenic (Sep 26, 2024) N Not contributing to aggregate classification	no assertion criteria provided	CFTR-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004105952.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: show The CFTR c.1521_1523delCTT variant is predicted to result in an in-frame deletion (p.Phe508del). This variant, frequently described as ΔF508, is known to disrupt protein function and is the most common cause of autosomal recessive cystic fibrosis (Riordan et al. 1989. PubMed ID: 2475911; Watson et al. 2004. PubMed ID: 15371902; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 1.2% of alleles in individuals of European (Non-Finnish) descent. In summary, we classify this variant as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jun 10, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Cystic fibrosis	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000536740.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Publications: PubMed (7) PubMed: 15141088‚ 15246977‚ 15371902‚ 17206681‚ 23974870‚ 24559724‚ 2475911 Observation: 1 Collection method: research Allele origin: maternal Affected status: unknown Observation 1 Collection method: research Allele origin: maternal Affected status: unknown

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744105.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

not provided (-) N Not contributing to aggregate classification	no classification provided	not provided	SNPedia Accession: SCV000090450.1 First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013	Observation: 1 Collection method: not provided Allele origin: germline Affected status: not provided Observation 1 Collection method: not provided Allele origin: germline Affected status: not provided

not provided (-) N Not contributing to aggregate classification	no classification provided	Cystic fibrosis	GeneReviews Accession: SCV001622798.2 First in ClinVar: May 23, 2021 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 15371902‚ 20301428 BookShelf: NBK1250 BookShelf: NBK1250 Observation: 1 Collection method: literature only Allele origin: unknown Affected status: unknown Observation 1 Collection method: literature only Allele origin: unknown Affected status: unknown

not provided (-) N Not contributing to aggregate classification	no classification provided	Hereditary pancreatitis	GeneReviews Accession: SCV000153744.3 First in ClinVar: May 30, 2014 Last updated: Oct 01, 2022	Publications: BookShelf: NBK190101 BookShelf: NBK190101 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes Observation 1 Collection method: literature only Allele origin: germline Affected status: yes

not provided (-) N Not contributing to aggregate classification	no classification provided	Cystic fibrosis	GenomeConnect, ClinGen Accession: SCV000607274.4 First in ClinVar: Apr 03, 2017 Last updated: Apr 13, 2025	Comment: show Variant reported in multiple GenomeConnect participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 10/28/2022 by ARUP Laboratories, INC, 06/29/2018 by Genetic Services Laboratory, University of Chicago, and 08/20/2015 by Mayo Clinic Genetic Testing Laboratories. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Observation: 3 Observation 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown Clinical Features: Myopia (present) , Abnormal curvature of the vertebral column (present) Indication for testing: Carrier Screening Zygosity: 1 Single Heterozygote Age: 30-39 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories, Mayo Clinic Date variant was reported to submitter: 2015-08-20 Testing laboratory interpretation: Pathogenic Observation 2 Collection method: phenotyping only Allele origin: unknown Affected status: unknown Clinical Features: Cardiomyopathy (present) , Attention deficit hyperactivity disorder (present) , Attention deficit hyperactivity disorder (present) Indication for testing: Diagnostic Zygosity: 1 Single Heterozygote Age: 10-19 years Sex: female Method: Exome Sequencing Testing laboratory: Genetic Services Laboratory, University of Chicago Date variant was reported to submitter: 2018-06-29 Testing laboratory interpretation: Pathogenic Observation 3 Collection method: phenotyping only Allele origin: unknown Affected status: unknown Clinical Features: Premature birth (present) , Hyperthyroidism (present) , Hypertonia (present) , Memory impairment (present) , Increased susceptibility to fractures (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Asthma (present) , Abnormality of the respiratory system (present) , Abnormal pattern of respiration (present) , Abnormal esophagus morphology (present) , Abnormal stomach morphology (present) , Abnormality of the pancreas (present) , Abnormality of the liver (present) , Abnormal intestine morphology (present) , Abnormality of urine homeostasis (present) , Abnormal inflammatory response (present) , Recurrent infections (present) , Abnormal thrombosis (present) , Abnormality of coagulation (present) , Bruising susceptibility (present) , Epistaxis (present) , Abnormal erythrocyte morphology (present) , Abnormal leukocyte morphology (present) Zygosity: 1 Single Heterozygote Age: 30-39 years Sex: male Method: Single Gene Sequencing Testing laboratory: ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Date variant was reported to submitter: 2022-10-28 Testing laboratory interpretation: Pathogenic

Comment:

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

Comment:

NM_000492.3(CFTR):c.1521_1523delCTT(aka F508del) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870 and 15371902. Classification of NM_000492.3(CFTR):c.1521_1523delCTT(aka F508del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

The p.Phe508del variant in CFTR (also known as ΔF508) is a deletion of a single amino acid at position 508 and is well-established as a pathogenic variant for autosomal recessive cystic fibrosis (Kerem 1989 PMID:2570460, Fuller 1992 PMID:1381146, Southern 1997 PMID:9135274, Grody 2001 PMID:11280952, Sosnay 2013 PMID:23974870). This is the most common pathogenic variant reported in CFTR and has been classified as Pathogenic by the ACMG practice guideline for cystic fibrosis carrier screening and the ClinGen-approved CFTR2 expert panel (ClinVar Variation ID 7105). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PS3, PM4_Supporting.

Comment:

The CFTR c.1521_1523del (p.Phe508del) variant (also known as F508del and Delta F508) is the most common cystic fibrosis (CF) pathogenic variant that accounts for approximately 70% of alleles in affected patients (PMIDs: 23974870 (2013), 23857699 (2013), 8886242 (1996), 38003474 (2023)). It causes a severe phenotype due to deleterious effects on CFTR protein maturation and function (PMIDs: 23974870 (2013), 25148434 (2014), 26581802 (2016)). This variant, being so common in European CF cohorts, has a general population frequency of 0.016 (807/50740 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)). Based on the available information, this variant is classified as pathogenic.

Comment:

The CFTR c.1521_1523del; p.Phe508del (F508del) variant is the most common pathogenic CFTR variant that has been reported in Caucasians (Sosnay 2013, CFTR2 database). This variant is considered to cause cystic fibrosis when identified with another pathogenic variant on the opposite chromosome. REFERENCES CFTR2 database: http://cftr2.org/ Sosnay P et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45(10):1160-7. PMID: 23974870.

Comment:

The c.1521_1523delCTT pathogenic variant in the CFTR gene (also known as p.Phe508del or delta F508) is the most common variant identified in the CFTR gene, with up to 90% of individuals with cystic fibrosis (CF) having at least one copy of the c.1521_1523delCTT variant (Cai et al., 2011). The c.1521_1523delCTT variant results in an in-frame deletion of a single Phenylalanine residue at codon 508. Individuals who are homozygous for the c.1521_1523delCTT variant demonstrate the classic features of CF, whereas individuals compound heterozygous for the c.1521_1523delCTT variant and another CFTR variant may have a modified disease phenotype (Ong et al., 2017). Heterozygous carriers of the c.1521_1523delCTT variant are usually asymptomatic, however, may be at increased risk for developing a CFTR-related disorder, as an increased prevalence of single CFTR pathogenic variants has been observed among individuals with chronic pulmonary conditions, CAVD and pancreatitis (Cuppens et al., 2004; Bombieri et al., 2011). We interpret the c.1521_1523delCTT variant as a pathogenic variant.

Comment:

A heterozygous inframe deletion variant, NM_000492.3(CFTR):c.1521_1523del, has been identified in exon 11 of 27 in the CFTR gene. The variant is predicted to result in an inframe deletion of a single amino acid at position 508 of the protein, NP_000483.3(CFTR):p.(Phe508del). The phenylalanine at this position has very high conservation (UCSC, 100 vertebrates), and is located in the ABC transporter 1 functional domain. This variant is present in the gnomAD database at a frequency of 0.7% (2027 heterozygotes, 1 homozygote), and has been previously reported multiple times in individuals with cystic fibrosis, being the most common causative variant in the CFTR gene (ClinVar; Egan, ME. et al. (2016)). Analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

Comment:

A Heterozygous inframe indel variant c.1520_1522delTCT in Exon 11 of the CFTR gene that results in the amino acid substitution p.Phe508del was identified. The observed variant has a minor allele frequency of 0.00707/0.00800% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic. (Variant ID 7105). This variant has been previously reported for Indian patients with congenital absence of the vas deferens by Sharma H et al., 2014. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

Comment:

This sequence change is an inframe deletion of 3 bp predicted to cause the deletion of phenylalanine at position 508 of the CFTR protein (p.Phe508del). The region deleted is highly conserved (100 vertebrates, UCSC) in a nonrepeat region, and is located in the ABC transporter domain. The variant is present in a large population cohort at a frequency of 0.7% (rs1297060838, 2,027/282,630 alleles, 1 homozygote in gnomAD v2.1). It is the most commonly reported pathongenic variant in CFTR, and is assigned a practice quideline pathogenic classification in ClinVar (ID: 7105). It has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in cystic fibrosis cases (PMID: 8092189, 1379413, 2570460). Additionally, a Cftr Phe508del/Phe508del mouse model lack CFTR in the apical membrane, were chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID: 7560099). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PM4_Supporting.

Comment:

This sequence variant is an in-frame deletion of 3 nucleotides spanning positions 1521 through 1523 of the coding sequence of the CFTR gene that removes Phe508 of the CF transmembrane conductance regulator protein. This is a previously reported (ClinVar 7105), well characterized variant (PMID: 15371902) that is the most common cystic fibrosis-associated variant in the general population (PMID: 23974870). The variant is also known as deltaF508 and similar identifiers in the literature and public databases. This variant is present in 2976 of 403344 alleles (0.7378%) in the gnomAD population dataset. Experimental evidence shows that function of the variant protein is significantly inhibited (PMID: 2475911). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM4, PS3, PS4

Comment:

The p.F508del pathogenic mutation (also known as deltaF508 and c.1521_1523delCTT) is located in coding exon 11 of the CFTR gene. This pathogenic mutation results from an in-frame CTT deletion at nucleotide positions 1521 to 1523. This results in the in-frame deletion of a phenylalanine at codon 508. This mutation is associated with elevated sweat chloride levels, lung disease, pancreatic insufficiency, and Pseudomonas infection; in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Disease expression is variable, even among individuals homozygous for p.F508del (Bronsveld I et al. J. Clin. Invest., 2001 Dec;108:1705-15). This mutation accounts for approximately 70% of cystic fibrosis chromosomes worldwide; it is a class II mutation which results in a misfolded CFTR protein that is subsequently degraded (Esposito S et al. Mol Cell Pediatr, 2016 Dec;3:13). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 30030066; 27738188) - PS3. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 7105; PMID: 30089726; 29614238; 29668297; 29944384) - PS4. The p.(Phe508del) was detected in trans with a pathogenic variant (PMID: 30089726; 29614238) - PM3_very strong. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4 and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

The CFTR c.1521_1523del (p.Phe508del) variant, also known as delta508, has been reported in the homozygous or trans heterozygous state in many individuals affected with cystic fibrosis and is the most commonly reported pathogenic variant (cftr2.org; Sosnay PR et al., PMID: 23974870). The ACMG practice guidelines classify this variant as pathogenic (ClinVar Variation ID: 7105). Additionally, a Cftr Phe508del homozygous mouse model recapitulates human disease (Zeiher BG et al., PMID: 7560099). The highest population minor allele frequency in the population database genome aggregation database (v.4.1.0) is 1.5% in the European (non-Finnish) population which is consistent with the carrier rate of cystic fibrosis. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Comment:

The variant is observed in the gnomAD v4.1.0 dataset (total allele frequency: 1.193%). Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26857764). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000007105 /PMID: 2475911 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This is an inframe substitution variant in the CFTR gene (OMIM: 602421). Pathogenic variants in this gene have been associated with autosomal recessive cystic fibrosis. This variant has been identified in the homozygous or compound heterozygous state in many unrelated affected individuals (PMID: 23974870). Functional studies have shown that this variant alters CFTR protein function (PMID: 21594800, 20628052, 25763566, 21152102, 26149808) (PS3). Other reputable laboratories have reported this variant as pathogenic or likely pathogenic, and this classification has been validated by an expert panel in ClinVar (PP5). This variant has a 1.4943% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal recessive cystic fibrosis.

Comment:

This variant, c.1521_1523delCTT, results in the deletion of 1 amino acid of the CFTR protein (p.Phe508del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs199826652, gnomAD 1.2%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with cystic fibrosis and is the most common cause of the condition (PMID: 2475911, 15371902, 23974870). It has also been observed to segregate with disease in related individuals. This variant is also known as deltaF508. ClinVar contains an entry for this variant (Variation ID: 7105). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CFTR function (PMID: 2475911, 23974870). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant is also known as deltaF508 and has been previously reported as the most common pathogenic variant in the CFTR gene (PMID: 35650428, 36498475). Functional studies have demonstrated that this variant disrupts the normal function of the protein (PMID: 2475911, 17873061). It is present in the gnomAD v4 population database at a frequency of 1.2% (19237/1612320), including 58 homozygotes. Based on the available evidence, the c.1521_1523del (p.Phe508del) variant is classified as Pathogenic.

Comment:

The c.1521_1523delCTT (p.Phe508del), also known as Î”F508, is an in-frame deletion in the CFTR gene. This variant is the most common CF-causing mutation, accounting for an estimated 72% of mutant alleles in people of European ancestry (Watson et al., 2004). This p.Phe508del variant is classified as a class II mutation that blocks the processing of the CFTR protein (Welsh et al., 2001). This variant has been reported at low frequencies (1.0%) in 1000 Genomes and ExAc population databases, but has not been reported in the Exome Sequencing Project database (ESP). The CFTR2 database has 32,833 patients that have this mutation, which they classify as CF-causing (http://www.cftr2.org/mutation.php?view=general&mutation_id=1). Therefore, this collective evidence supports the classification of the c.1521_1523delCTT (p.Phe508del) as a recessive pathogenic variant for Cystic fibrosis.

Comment:

The inframe deletion c.1521_1523del (p.Phe508del) variant in the CFTR gene has been reported previously in multiple individuals in homozygous/compound heterozygous state affected with Cystic fibrosis related disorders (Sosnay et al., 2013; Terlizzi et al., 2021). The p.Phe508del variant is the most frequent deletion that occurs in ~85% of Cystic fibrosis patients worldwide and is described to affect CFTR (class II) protein processing (Awatade et al. 2019). Experimental studies have shown that this variant affects CFTR function (Zeiher et al. 1995). The p.Phe508del variant is reported with an allele frequency of 0.7% in the gnomAD exomes database and is novel (not in any individuals) in the 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This p.Phe508del causes the deletion of the amino acid Phenylalanine at position 508. For these reasons, this variant has been classified as Pathogenic.

Comment:

The observed inframe deletion c.1521_1523del p.Phe508del variant in the CFTR gene has been reported previously in multiple individuals in homozygous/ compound heterozygous state affected with Cystic fibrosis. Experimental studies have shown that this variant affects CFTR function Sosnay et al., 2013; Terlizzi et al., 2021. The p.Phe508del variant is the most frequent deletion that occurs in ~85% of Cystic fibrosis patients worldwide and is described to affect CFTR class II protein processing. The p.Phe508del variant is reported with an allele frequency of 0.7% in the gnomAD exomes database and is novel not in any individuals in the 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This p.Phe508del causes the deletion of the amino acid Phenylalanine at position 508. For these reasons, this variant has been classified as Pathogenic.

Comment:

This sequence change is an inframe deletion of 3 bp predicted to cause the deletion of phenylalanine at position 508 of the CFTR protein, p.(Phe508del). The region deleted is highly conserved (100 vertebrates, Multiz Alignments) in a nonrepeat region, and is located in the ABC transporter domain. The highest population minor allele frequency in the population database gnomAD v4.1 is 1.5% (17,610/1,178,514 alleles, 49 homozygotes) in the European (non-Finnish) population. It is the most commonly reported pathogenic variant in CFTR and is assigned a practice guideline pathogenic classification (ClinVar ID: 7105). It has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in cystic fibrosis cases and segregates with disease in multiple families (PMID: 8092189, 1379413, 2570460, 25910067). Additionally, a Cftr Phe508del/Phe508del mouse model lacks CFTR in the apical membrane, was chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID: 7560099). Based on the classification scheme RMH ACMG Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Moderate, PM4_Supporting, BS1.

Comment:

A homozygous 3 base pair deletion in exon 11 of the CFTR gene that results in the in-frame deletion of Phenylalanine was detected. The observed variant c.1521_1523del (p.Phe508del) has a minor allele frequency of 0.4% and 0.68% in the 1000 Genomes and ExAC databases respectively. The observed variation has previously been identified in patients affected with cystic fibrosis and it lies in the ABC transporter domain of the CFTR protein (Riordan et al 1989). The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.

Comment:

The CFTR p.F508del variant is the most common variant known to cause cystic fibrosis (CF); this variant acounts for ~70% of CFTR variants and is present in approximately 85% of CF patients worldwide (Maiuri_2015_PMID:26046070). The variant was identified in dbSNP (ID: rs113993960) and ClinVar (classified as pathogenic by the American College of Medical Genetics and Genomics, Laboratory for Molecular Medicine and 20+ other laboratories). The variant was identified in control databases in 2027 of 282630 chromosomes (1 homozygous) at a frequency of 0.007172 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1598 of 129034 chromosomes (freq: 0.01238), Other in 49 of 7214 chromosomes (freq: 0.006792), Ashkenazi Jewish in 58 of 10368 chromosomes (freq: 0.005594), Latino in 135 of 35426 chromosomes (freq: 0.003811), African in 65 of 24958 chromosomes (freq: 0.002604), European (Finnish) in 61 of 25074 chromosomes (freq: 0.002433) and South Asian in 61 of 30608 chromosomes (freq: 0.001993), but was not observed in the East Asian population. This variant is an in-frame deletion resulting in the removal of a phenylalanine (F) residue at codon 508; the deletion of p.F508 results in a misfolded mutant protein that is prematurely degraded before it reaches the plasma membrane (Maiuri_2015_PMID:26046070). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Comment:

The CFTR c.1521_1523delCTT variant is predicted to result in an in-frame deletion (p.Phe508del). This variant, frequently described as ΔF508, is known to disrupt protein function and is the most common cause of autosomal recessive cystic fibrosis (Riordan et al. 1989. PubMed ID: 2475911; Watson et al. 2004. PubMed ID: 15371902; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 1.2% of alleles in individuals of European (Non-Finnish) descent. In summary, we classify this variant as pathogenic.

Comment:

Variant reported in multiple GenomeConnect participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 10/28/2022 by ARUP Laboratories, INC, 06/29/2018 by Genetic Services Laboratory, University of Chicago, and 08/20/2015 by Mayo Clinic Genetic Testing Laboratories. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis.	Silva Filho LVRFD	Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia	2024	PMID: 38198345
Cystic Fibrosis.	Adam MP	-	2024	PMID: 20301428
Pathogenic Variants and Genotypes of the CFTR Gene in Russian Men with Cystic Fibrosis and CBAVD Syndrome.	Chernykh V	International journal of molecular sciences	2023	PMID: 38003474
FarGen: Elucidating the distribution of coding variants in the isolated population of the Faroe Islands.	Mortensen Ó	European journal of human genetics : EJHG	2023	PMID: 36404349
Cystic Fibrosis Patients with F508del/Minimal Function Genotype: Laboratory and Nutritional Evaluations after One Year of Elexacaftor/Tezacaftor/Ivacaftor Treatment.	Carnovale V	Journal of clinical medicine	2022	PMID: 36498475
Splicing mutations in the CFTR gene as therapeutic targets.	Deletang K	Gene therapy	2022	PMID: 35650428
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Ex vivo model predicted in vivo efficacy of CFTR modulator therapy in a child with rare genotype.	Terlizzi V	Molecular genetics & genomic medicine	2021	PMID: 33713579
Impact of integrated translational research on clinical exome sequencing.	Klee EW	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33144682
EX18_21 large duplication: A novel pathogenic mutation of the CFTR gene for cystic fibrosis.	Niemyjski EA	Pediatric pulmonology	2021	PMID: 33118704
Prenatal Diagnosis for Primary Immunodeficiency Disorders-An Overview of the Indian Scenario.	Yadav RM	Frontiers in immunology	2020	PMID: 33365035
Pituitary stalk interruption syndrome is characterized by genetic heterogeneity.	Brauner R	PloS one	2020	PMID: 33270637
Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.	Cheema H	NPJ genomic medicine	2020	PMID: 33083013
Pseudo-Bartter syndrome in Chinese children with cystic fibrosis: Clinical features and genotypic findings.	Shen Y	Pediatric pulmonology	2020	PMID: 32761997
Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.	Petrova NV	Genes	2020	PMID: 32429104
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions.	Miller AC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31882447
Pancreatitis Overview.	Adam MP	-	2020	PMID: 24624459
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Cystic Fibrosis Mutation Spectrum in North Macedonia: A Step Toward Personalized Therapy.	Terzic M	Balkan journal of medical genetics : BJMG	2019	PMID: 31523618
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: agibbs@bcm.edu	American journal of human genetics	2019	PMID: 31447099
CFTR gene variants: a predisposition factor to aquagenic palmoplantar keratoderma.	Raynal C	The British journal of dermatology	2019	PMID: 31310009
Identification of a novel large deletion and other copy number variations in the CFTR gene in patients with Cystic Fibrosis from a multiethnic population.	Martins RDS	Molecular genetics & genomic medicine	2019	PMID: 31199594
Cystic fibrosis presentation in del. F508 and p. Tyr109Glyfs compound heterozygote CFTR state: a case report.	Turkalj M	Croatian medical journal	2019	PMID: 31187952
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.	Monies D	American journal of human genetics	2019	PMID: 31130284
Phenotypic spectrum and genetic heterogeneity of cystic fibrosis in Sri Lanka.	Indika NLR	BMC medical genetics	2019	PMID: 31126253
Sequencing as a first-line methodology for cystic fibrosis carrier screening.	Beauchamp KA	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31036917
Development of a Novel Next-Generation Sequencing Assay for Carrier Screening in Old Order Amish and Mennonite Populations of Pennsylvania.	Crowgey EL	The Journal of molecular diagnostics : JMD	2019	PMID: 31028937
Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests.	Thauvin-Robinet C	European journal of human genetics : EJHG	2019	PMID: 31019283
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.	Ceyhan-Birsoy O	American journal of human genetics	2019	PMID: 30609409
Functional analysis of the p.[Arg74Trp;Val201Met;Asp1270Asn]/p.Phe508del CFTR mutation genotype in human native colon.	Schucht S	Molecular genetics & genomic medicine	2019	PMID: 30600599
Phenotypic spectrum of patients with cystic fibrosis and cystic fibrosis-related disease carrying p.Arg117His.	Keenan K	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2019	PMID: 30279124
R560S: A class II CFTR mutation that is not rescued by current modulators.	Awatade NT	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2019	PMID: 30030066
Cystic fibrosis in Tunisian children: a review of 32 children.	Boussetta K	African health sciences	2018	PMID: 30602999
High-frequency actionable pathogenic exome variants in an average-risk cohort.	Rego S	Cold Spring Harbor molecular case studies	2018	PMID: 30487145
Ivacaftor-induced sweat chloride reductions correlate with increases in airway surface liquid pH in cystic fibrosis.	Abou Alaiwa MH	JCI insight	2018	PMID: 30089726
Clinical Characteristics and Predictors of Reduced Survival for Adult-diagnosed Cystic Fibrosis. Analysis of the Canadian CF Registry.	Desai S	Annals of the American Thoracic Society	2018	PMID: 29944384
Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity.	Raraigh KS	American journal of human genetics	2018	PMID: 29805046
PLCB3 Loss of Function Reduces Pseudomonas aeruginosa-Dependent IL-8 Release in Cystic Fibrosis.	Rimessi A	American journal of respiratory cell and molecular biology	2018	PMID: 29668297
Changes in Lung Clearance Index in Preschool-aged Patients with Cystic Fibrosis Treated with Ivacaftor (GOAL): A Clinical Trial.	Ratjen F	American journal of respiratory and critical care medicine	2018	PMID: 29614238
Spectrum of CFTR gene sequence variants in a northern Portugal population.	Grangeia A	Pulmonology	2018	PMID: 29589582
First experience in Switzerland in Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease enrolled in a lumacaftor-ivacaftor therapy trial - preliminary results.	Murer C	Swiss medical weekly	2018	PMID: 29451946
The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.	Reuter MS	CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne	2018	PMID: 29431110
Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis.	Graeber SY	American journal of respiratory and critical care medicine	2018	PMID: 29327948
Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests.	Archibald AD	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29261177
Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR.	Taylor-Cousar JL	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2018	PMID: 29126871
Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR.	Donaldson SH	American journal of respiratory and critical care medicine	2018	PMID: 28930490
Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del.	Taylor-Cousar JL	The New England journal of medicine	2017	PMID: 29099344
Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis.	Rowe SM	The New England journal of medicine	2017	PMID: 29099333
A Link Between a Common Mutation in CFTR and Impaired Innate and Adaptive Viral Defense.	Svedin E	The Journal of infectious diseases	2017	PMID: 28968805
Patients with Cystic Fibrosis and a G551D or Homozygous F508del Mutation: Similar Lung Function Decline.	Sawicki GS	American journal of respiratory and critical care medicine	2017	PMID: 28617084
Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial.	Ratjen F	The Lancet. Respiratory medicine	2017	PMID: 28606620
A comprehensive strategy for exome-based preconception carrier screening.	Sallevelt SCEH	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28492530
Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease.	Hubert D	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2017	PMID: 28325531
Applying Cystic Fibrosis Transmembrane Conductance Regulator Genetics and CFTR2 Data to Facilitate Diagnoses.	Sosnay PR	The Journal of pediatrics	2017	PMID: 28129809
Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR.	Rowe SM	Annals of the American Thoracic Society	2017	PMID: 27898234
Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR.	Milla CE	American journal of respiratory and critical care medicine	2017	PMID: 27805836
Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles.	Terlizzi V	Journal of medical genetics	2017	PMID: 27738188
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.	Stray-Pedersen A	The Journal of allergy and clinical immunology	2017	PMID: 27577878
The Etiology and Clinical Course of Chronic Pancreatitis in Children With Early Onset of the Disease.	Wejnarska K	Journal of pediatric gastroenterology and nutrition	2016	PMID: 27673710
Analysis of cystic fibrosis-associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseases.	Sabusap CM	JCI insight	2016	PMID: 27660821
Molecular Genetics of Cystic Fibrosis Transmembrane Conductance Regulator: Genotype and Phenotype.	Sosnay PR	Pediatric clinics of North America	2016	PMID: 27469177
Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.	Dekkers JF	Science translational medicine	2016	PMID: 27334259
Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis.	Elborn JS	The Lancet. Respiratory medicine	2016	PMID: 27298017
Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis.	Palermo JJ	Pancreas	2016	PMID: 27171515
Molecular screening of CFTR gene in Egyptian patients with congenital bilateral absence of the vas deferens: a preliminary study.	Fathy M	Andrologia	2016	PMID: 26989879
Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis.	Esposito S	Molecular and cellular pediatrics	2016	PMID: 26976279
The novel complex allele [A238V;F508del] of the CFTR gene: clinical phenotype and possible implications for cystic fibrosis etiological therapies.	Diana A	Journal of human genetics	2016	PMID: 26911355
Genetics of Cystic Fibrosis: Clinical Implications.	Egan ME	Clinics in chest medicine	2016	PMID: 26857764
c.3623G > A mutation encodes a CFTR protein with impaired channel function.	Zhang X	Respiratory research	2016	PMID: 26800689
Pharmacological Correction of Cystic Fibrosis: Molecular Mechanisms at the Plasma Membrane to Augment Mutant CFTR Function.	Arora K	Current drug targets	2016	PMID: 26648081
Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop.	Ehrhardt A	The Journal of biological chemistry	2016	PMID: 26627831
Lumacaftor alone and combined with ivacaftor: preclinical and clinical trial experience of F508del CFTR correction.	Brewington JJ	Expert review of respiratory medicine	2016	PMID: 26581802
Cystic fibrosis.	Ratjen F	Nature reviews. Disease primers	2015	PMID: 27189798
∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.	Pankow S	Nature	2015	PMID: 26618866
Newborn Screening for Cystic Fibrosis in California.	Kharrazi M	Pediatrics	2015	PMID: 26574590
Deletion of Phenylalanine 508 in the First Nucleotide-binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator Increases Conformational Exchange and Inhibits Dimerization.	Chong PA	The Journal of biological chemistry	2015	PMID: 26149808
Genotype-phenotype relationship in Iranian patients with cystic fibrosis.	Najafi M	The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology	2015	PMID: 26006199
Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.	Wainwright CE	The New England journal of medicine	2015	PMID: 25981758
A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis.	Lucarelli M	Molecular medicine (Cambridge, Mass.)	2015	PMID: 25910067
Should diffuse bronchiectasis still be considered a CFTR-related disorder?	Bergougnoux A	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2015	PMID: 25797027
Impact of the F508del mutation on ovine CFTR, a Cl- channel with enhanced conductance and ATP-dependent gating.	Cai Z	The Journal of physiology	2015	PMID: 25763566
Relationship between CFTR and CTRC variants and the clinical phenotype in late-onset cystic fibrosis disease with chronic pancreatitis.	Tomaiuolo AC	The Journal of molecular diagnostics : JMD	2015	PMID: 25636364
Necrotising pneumonia and bronchiectasis in a previously healthy 30-year-old man.	Blauvelt DG	BMJ case reports	2015	PMID: 25608981
The major cystic fibrosis causing mutation exhibits defective propensity for phosphorylation.	Pasyk S	Proteomics	2015	PMID: 25330774
Function, pharmacological correction and maturation of new Indian CFTR gene mutations.	Sharma H	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2015	PMID: 25042876
[Phenotypic variability of cystic fibrosis: case report of twins with F508/F508 mutation].	Hernández-Amaris MF	Revista chilena de pediatria	2014	PMID: 25697321
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators protect G551D but not ΔF508 CFTR from thermal instability.	Liu X	Biochemistry	2014	PMID: 25148434
A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial.	Boyle MP	The Lancet. Respiratory medicine	2014	PMID: 24973281
Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers.	Sharma H	Molecular human reproduction	2014	PMID: 24958810
Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models.	Wang Y	The international journal of biochemistry & cell biology	2014	PMID: 24727426
Mutation Analysis of Exons 10 and 17a of CFTR Gene in Patients with Cystic Fibrosis in Kermanshah Province, Western Iran.	Sahami A	Journal of reproduction & infertility	2014	PMID: 24696795
Association of cystic fibrosis transmembrane-conductance regulator gene mutation with negative outcome of intracytoplasmic sperm injection pregnancy in cases of congenital bilateral absence of vas deferens.	Lu S	Fertility and sterility	2014	PMID: 24559724
The relative frequency of CFTR mutation classes in European patients with cystic fibrosis.	De Boeck K	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2014	PMID: 24440181
Cystic fibrosis as a rare cause of apple peel syndrome.	Broekaert IJ	Klinische Padiatrie	2014	PMID: 24435787
Lethal course of meconium ileus in preterm twins revealing a novel cystic fibrosis mutation (p.Cys524Tyr).	Puzik A	BMC pediatrics	2014	PMID: 24433235
Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.	Van Goor F	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2014	PMID: 23891399
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients.	Masson E	PloS one	2013	PMID: 23951356
The silent codon change I507-ATC->ATT contributes to the severity of the ΔF508 CFTR channel dysfunction.	Lazrak A	FASEB journal : official publication of the Federation of American Societies for Experimental Biology	2013	PMID: 23907436
Early acute pancreatitis in a child with compound heterozygosis ∆F508/R1438W/Y1032C cystic fibrosis: a case report.	Leonardi S	Journal of medical case reports	2013	PMID: 23883480
Screening for F508del as a first step in the molecular diagnosis of cystic fibrosis.	Marson FA	Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia	2013	PMID: 23857699
Analysis of CFTR Gene Variants in Idiopathic Bronchiectasis in Serbian Children.	Milosevic K	Pediatric allergy, immunology, and pulmonology	2013	PMID: 23781395
Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants.	Hamoir C	Digestion	2013	PMID: 23751316
A novel case of diabetic muscle necrosis in a patient with cystic fibrosis-related diabetes.	Chalasani S	Clinical medicine & research	2013	PMID: 23656801
Regulation of cystic fibrosis transmembrane conductance regulator by microRNA-145, -223, and -494 is altered in ΔF508 cystic fibrosis airway epithelium.	Oglesby IK	Journal of immunology (Baltimore, Md. : 1950)	2013	PMID: 23436935
Atypical form of transient reactive papulotranslucent acrokeratoderma in a cystic fibrosis carrier.	Baquerizo K	Journal of cutaneous pathology	2013	PMID: 23379606
CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.	Thauvin-Robinet C	Journal of medical genetics	2013	PMID: 23378603
Impaired CFTR function in mild cystic fibrosis associated with the S977F/T5TG12complex allele in trans with F508del mutation.	Sorio C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2013	PMID: 23361109
Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein.	He L	FASEB journal : official publication of the Federation of American Societies for Experimental Biology	2013	PMID: 23104983
CFTR mutations altering CFTR fragmentation.	Tosoni K	The Biochemical journal	2013	PMID: 23067305
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.	Lazarin GA	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22975760
CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?	Rosendahl J	Gut	2013	PMID: 22427236
Effect of maternal cystic fibrosis genotype on diabetes in pregnancy.	Giacobbe LE	Obstetrics and gynecology	2012	PMID: 23168765
The ΔF508-CFTR mutation inhibits wild-type CFTR processing and function when co-expressed in human airway epithelia and in mouse nasal mucosa.	Tucker TA	BMC physiology	2012	PMID: 22999299
A population-based study of autosomal-recessive disease-causing mutations in a founder population.	Chong JX	American journal of human genetics	2012	PMID: 22981120
Thermal instability of ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) channel function: protection by single suppressor mutations and inhibiting channel activity.	Liu X	Biochemistry	2012	PMID: 22680785
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis.	Ooi CY	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2012	PMID: 22658665
The cystic-fibrosis-associated ΔF508 mutation confers post-transcriptional destabilization on the C. elegans ABC transporter PGP-3.	He L	Disease models & mechanisms	2012	PMID: 22569626
The F508del mutation in cystic fibrosis transmembrane conductance regulator gene impacts bone formation.	Le Henaff C	The American journal of pathology	2012	PMID: 22449949
Management of male infertility due to congenital bilateral absence of vas deferens should not ignore the diagnosis of cystic fibrosis.	Grzegorczyk V	Andrologia	2012	PMID: 22390181
Pulmonary Mycobacterium abscessus: a canary in the cystic fibrosis coalmine.	Haverkamp MH	The Journal of infection	2012	PMID: 22366207
Cystic fibrosis transmembrane conductance regulator gene abnormalities in patients with asthma and recurrent neutrophilic bronchitis.	Goodwin J	Canadian respiratory journal	2012	PMID: 22332135
CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systemic review and meta-analysis.	Yu J	Human reproduction (Oxford, England)	2012	PMID: 22081250
Extensive molecular analysis of patients bearing CFTR-related disorders.	Amato F	The Journal of molecular diagnostics : JMD	2012	PMID: 22020151
[CFTR F508DEL mutation and 5T allele in patients with chronic pancreatitis and pancreatic adenocarcinoma].	Nikolić A	Acta chirurgica Iugoslavica	2011	PMID: 22369017
Evidence for alteration of calpain/calpastatin system in PBMC of cystic fibrosis patients.	Averna M	Biochimica et biophysica acta	2011	PMID: 21983488
The prevalence of common CFTR mutations in Iranian infertile men with non-CAVD obstructive azoospermia by using ARMS PCR techniques.	Safinejad K	Journal of assisted reproduction and genetics	2011	PMID: 21976147
Thermally unstable gating of the most common cystic fibrosis mutant channel (ΔF508): "rescue" by suppressor mutations in nucleotide binding domain 1 and by constitutive mutations in the cytosolic loops.	Wang W	The Journal of biological chemistry	2011	PMID: 21965669
F508del-CFTR increases intracellular Ca(2+) signaling that causes enhanced calcium-dependent Cl(-) conductance in cystic fibrosis.	Martins JR	Biochimica et biophysica acta	2011	PMID: 21907281
Recommendations for the classification of diseases as CFTR-related disorders.	Bombieri C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2011	PMID: 21658649
Application of high-resolution single-channel recording to functional studies of cystic fibrosis mutants.	Cai Z	Methods in molecular biology (Clifton, N.J.)	2011	PMID: 21594800
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.	Steiner B	Human mutation	2011	PMID: 21520337
The most common cystic fibrosis-associated mutation destabilizes the dimeric state of the nucleotide-binding domains of CFTR.	Jih KY	The Journal of physiology	2011	PMID: 21486785
The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs.	Ostedgaard LS	Science translational medicine	2011	PMID: 21411740
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
Calpain digestion and HSP90-based chaperone protection modulate the level of plasma membrane F508del-CFTR.	Averna M	Biochimica et biophysica acta	2011	PMID: 21111762
CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR.	Sheridan MB	Journal of medical genetics	2011	PMID: 21097845
Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis.	Schneider A	Gastroenterology	2011	PMID: 20977904
CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening.	Chávez-Saldaña M	Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion	2010	PMID: 21416780
The primary folding defect and rescue of ΔF508 CFTR emerge during translation of the mutant domain.	Hoelen H	PloS one	2010	PMID: 21152102
Cell Biology. The proteome in balance.	Hutt D	Science (New York, N.Y.)	2010	PMID: 20705837
Functional analysis of F508del CFTR in native human colon.	van Barneveld A	Biochimica et biophysica acta	2010	PMID: 20696241
Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis.	Wang C	Protein science : a publication of the Protein Society	2010	PMID: 20687163
The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis.	Thibodeau PH	The Journal of biological chemistry	2010	PMID: 20667826
A synonymous single nucleotide polymorphism in DeltaF508 CFTR alters the secondary structure of the mRNA and the expression of the mutant protein.	Bartoszewski RA	The Journal of biological chemistry	2010	PMID: 20628052
[Cystic fibrosis in a woman aged seventy].	Ras JE	Nederlands tijdschrift voor geneeskunde	2010	PMID: 20619026
Peripheral protein quality control removes unfolded CFTR from the plasma membrane.	Okiyoneda T	Science (New York, N.Y.)	2010	PMID: 20595578
Cystic fibrosis transmembrane conductance regulator gene mutation and lung cancer risk.	Li Y	Lung cancer (Amsterdam, Netherlands)	2010	PMID: 20116881
Cystic fibrosis transmembrane regulator fragments with the Phe508 deletion exert a dual allosteric control over the master kinase CK2.	Pagano MA	The Biochemical journal	2010	PMID: 19925455
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma.	McWilliams RR	Cancer	2010	PMID: 19885835
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners.	Gallati S	Reproductive biomedicine online	2009	PMID: 20021716
Deletion of Phe508 in the first nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator increases its affinity for the heat shock cognate 70 chaperone.	Scott-Ward TS	The FEBS journal	2009	PMID: 19878303
Disease-causing mutations in the cystic fibrosis transmembrane conductance regulator determine the functional responses of alveolar macrophages.	Deriy LV	The Journal of biological chemistry	2009	PMID: 19837664
Clinical and molecular characterization of S1118F-CFTR.	Penmatsa H	Pediatric pulmonology	2009	PMID: 19774621
Rare F311L CFTR gene mutation in a child presented with recurrent electrolyte abnormalities and metabolic alkalosis: case report.	Lumpaopong A	Journal of the Medical Association of Thailand = Chotmaihet thangphaet	2009	PMID: 19459534
Transient correction of the basic defect in sweat glands in an individual with cystic fibrosis carrying the complex CFTR allele F508del-R553Q.	Tümmler B	Thorax	2009	PMID: 19176844
Screening for liver disease in cystic fibrosis: analysis of clinical and genetic risk factors for its development.	Fustik S	The Turkish journal of pediatrics	2008	PMID: 19227414
CFTR mutation analysis of a Caucasian father with congenital bilateral absence of vas deferens, a Taiwanese mother, and twins resulting from ICSI procedure.	Chiang HS	Journal of the Formosan Medical Association = Taiwan yi zhi	2008	PMID: 18796364
Could a defective epithelial sodium channel lead to bronchiectasis.	Fajac I	Respiratory research	2008	PMID: 18507830
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.	Castellani C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 18456578
Respiratory exacerbations in childhood associated with compound heterozygosity Phe508del/Arg117His-7T of the cystic fibrosis transmembrane regulator gene.	Lee TW	Acta paediatrica (Oslo, Norway : 1992)	2008	PMID: 18394117
DeltaF508 mutation increases conformational flexibility of CFTR protein.	Wieczorek G	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 18234567
Diagnosis of atypical CF: a case-report to reflect.	Alghisi F	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 18180206
Processing and function of CFTR-DeltaF508 are species-dependent.	Ostedgaard LS	Proceedings of the National Academy of Sciences of the United States of America	2007	PMID: 17873061
Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens.	Grangeia A	Genetics in medicine : official journal of the American College of Medical Genetics	2007	PMID: 17413420
Potential role for the common cystic fibrosis DeltaF508 mutation in Crohn's disease.	Bresso F	Inflammatory bowel diseases	2007	PMID: 17206681
[Role of deep seminal tract imaging in the diagnosis of unilateral agenesis of the vas deferens. Case report of a patient with CFTR gene mutation].	Marcelli F	Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie	2006	PMID: 17175965
Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis.	Xu N	Journal of nephrology	2006	PMID: 17048214
Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection.	Ziedalski TM	Chest	2006	PMID: 17035430
The ABC protein turned chloride channel whose failure causes cystic fibrosis.	Gadsby DC	Nature	2006	PMID: 16554808
Phenotypic discordance in three siblings affected by atypical cystic fibrosis with the F508del/D614G genotype.	Castaldo G	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2006	PMID: 16478680
Mild cystic fibrosis revealed by persistent hyponatremia during the French 2003 heat wave, associated with the S1455X C-terminus CFTR mutation.	Epaud R	Clinical genetics	2005	PMID: 16283887
Analysis of most common CFTR mutations in patients affected by nasal polyps.	Kostuch M	European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery	2005	PMID: 16075239
Mutation spectrum of the CFTR gene in Taiwanese patients with congenital bilateral absence of the vas deferens.	Wu CC	Human reproduction (Oxford, England)	2005	PMID: 15905293
Reduced bone density in cystic fibrosis: DeltaF508 mutation is an independent risk factor.	King SJ	The European respiratory journal	2005	PMID: 15640323
Fcgamma receptor IIA genotype and susceptibility to P. aeruginosa infection in patients with cystic fibrosis.	De Rose V	European journal of human genetics : EJHG	2005	PMID: 15367919
The necessity of complete CFTR mutational analysis of an infertile couple before in vitro fertilization.	Wong LJ	Fertility and sterility	2004	PMID: 15482777
Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.	Watson MS	Genetics in medicine : official journal of the American College of Medical Genetics	2004	PMID: 15371902
Role of Cftr genotype in the response to chronic Pseudomonas aeruginosa lung infection in mice.	van Heeckeren AM	American journal of physiology. Lung cellular and molecular physiology	2004	PMID: 15246977
Rescuing cystic fibrosis transmembrane conductance regulator (CFTR)-processing mutants by transcomplementation.	Cormet-Boyaka E	Proceedings of the National Academy of Sciences of the United States of America	2004	PMID: 15141088
Cystic fibrosis: an unusual cause of chronic pancreatitis.	Vanderbruggen K	Acta gastro-enterologica Belgica	2003	PMID: 14618962
A cystic fibrosis patient with two novel mutations in mitochondrial DNA: mild disease led to delayed diagnosis of both disorders.	Wong LJ	American journal of medical genetics	2002	PMID: 12400067
Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings.	Bronsveld I	The Journal of clinical investigation	2001	PMID: 11733566
[Cystic fibrosis and normal sweat chloride values: a case-report].	Lebecque P	Revue des maladies respiratoires	2001	PMID: 11547256
Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.	Grody WW	Genetics in medicine : official journal of the American College of Medical Genetics	2001	PMID: 11280952
Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study.	Monaghan KG	American journal of medical genetics	2000	PMID: 11186891
Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis.	Ockenga J	The American journal of gastroenterology	2000	PMID: 10950058
Identification of cystic fibrosis mutations in Oman.	Frossard PM	Clinical genetics	2000	PMID: 10782933
Geographic distribution of cystic fibrosis transmembrane regulator gene mutations in Saudi Arabia.	Banjar H	Eastern Mediterranean health journal = La revue de sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq al-mutawassit	1999	PMID: 11924117
[Coexistence of cystic fibrosis and celiac disease. Description of a clinical case and review of the literature].	Venuta A	La Pediatria medica e chirurgica : Medical and surgical pediatrics	1999	PMID: 10963013
Cystic fibrosis patients with the 3272-26A-->G mutation have mild disease, leaky alternative mRNA splicing, and CFTR protein at the cell membrane.	Beck S	Human mutation	1999	PMID: 10425036
Pitfall in the use of genotype analysis as the sole diagnostic criterion for cystic fibrosis.	Chmiel JF	Pediatrics	1999	PMID: 10103316
Phenotypic variability in five cystic fibrosis patients compound heterozygous for the Y1092X mutation.	De Braekeleer M	Human heredity	1998	PMID: 9618063
[Two cases of cystic fibrosis in Japanese/German twins].	Hojo S	Nihon Kyobu Shikkan Gakkai zasshi	1997	PMID: 9493456
High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes.	Casals T	Human genetics	1997	PMID: 9439669
CFTR gene mutations in adults with disseminated bronchiectasis.	Girodon E	European journal of human genetics : EJHG	1997	PMID: 9272738
[Mucoviscidosis with respiratory symptomatology in the neonatal period].	Lamy S	Acta medica portuguesa	1997	PMID: 9235853
delta F508 in cystic fibrosis: willing but not able.	Southern KW	Archives of disease in childhood	1997	PMID: 9135274
Genealogy and geographical distribution of CFTR mutations in Saguenay Lac-Saint-Jean (Quebec, Canada).	De Braekeleer M	Annals of human biology	1996	PMID: 8886242
Complex cystic fibrosis allele R334W-R1158X results in reduced levels of correctly processed mRNA in a pancreatic sufficient patient.	Duarte A	Human mutation	1996	PMID: 8844211
Mild CF in a delta F508/R347H compound heterozygote woman: does the manifestation of this genotype differ in the two sexes?	Kosztolányi G	Clinical genetics	1996	PMID: 8740923
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis.	Miller PW	American journal of human genetics	1996	PMID: 8659542
High incidence of cystic fibrosis on the Faroe Islands: a molecular and genealogical study.	Schwartz M	Human genetics	1995	PMID: 7789957
A mouse model for the delta F508 allele of cystic fibrosis.	Zeiher BG	The Journal of clinical investigation	1995	PMID: 7560099
A change in gating mode leading to increased intrinsic Cl- channel activity compensates for defective processing in a cystic fibrosis mutant corresponding to a mild form of the disease.	Champigny G	The EMBO journal	1995	PMID: 7540133
Analysis of linkage disequilibrium between different cystic fibrosis mutations and three intragenic microsatellites in the Italian population.	Russo MP	Human mutation	1995	PMID: 7537148
Normal sweat chloride values do not exclude the diagnosis of cystic fibrosis.	Stewart B	American journal of respiratory and critical care medicine	1995	PMID: 7533604
Identification of the I507 deletion by site-directed mutagenesis.	Orozco L	American journal of medical genetics	1994	PMID: 8092189
A cystic fibrosis patient with delta F508, G542X and a deletion at the D7S8 locus.	Wagner K	Human mutation	1994	PMID: 7517267
Genetic analysis of Hispanic individuals with cystic fibrosis.	Grebe TA	American journal of human genetics	1994	PMID: 7509564
GeneReviews(®)	Adam MP	-	1993	PMID: 20301295
Cystic fibrosis mutations in French Canadians: three CFTR mutations are relatively frequent in a Quebec population with an elevated incidence of cystic fibrosis.	Rozen R	American journal of medical genetics	1992	PMID: 1536179
Mutation analysis of the cystic fibrosis transmembrane regulator gene in Native American populations of the southwest.	Grebe TA	American journal of human genetics	1992	PMID: 1384321
CFTR!	Fuller CM	The American journal of physiology	1992	PMID: 1381146
Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive.	Denning GM	Nature	1992	PMID: 1380673
Cystic fibrosis patients bearing both the common missense mutation Gly----Asp at codon 551 and the delta F508 mutation are clinically indistinguishable from delta F508 homozygotes, except for decreased risk of meconium ileus.	Hamosh A	American journal of human genetics	1992	PMID: 1379413
Cystic fibrosis mutations delta F508 and G542X in Jewish patients.	Lerer I	Journal of medical genetics	1992	PMID: 1377276
Cystic fibrosis in the Basque country: high frequency of mutation delta F508 in patients of Basque origin.	Casals T	American journal of human genetics	1992	PMID: 1370875
A pooling strategy for heterozygote screening of the delta F508 cystic fibrosis mutation.	Gille C	Human genetics	1991	PMID: 1997384
Genetic epidemiology of cystic fibrosis in Saguenay-Lac-St-Jean (Quebec, Canada).	Daigneault J	Clinical genetics	1991	PMID: 1756602
Nine mutations in the cystic fibrosis (CF) gene account for 80% of the CF chromosomes in French patients.	Simon-Bouy B	Clinical genetics	1991	PMID: 1723032
Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene.	Dörk T	Human genetics	1991	PMID: 1715308
Frequency of the phenylalanine deletion (delta F508) in the CF gene of Belgian cystic fibrosis patients.	Wauters JG	Clinical genetics	1991	PMID: 1673094
Worldwide survey of the delta F508 mutation--report from the cystic fibrosis genetic analysis consortium.	-	American journal of human genetics	1990	PMID: 2378364
PCR test for cystic fibrosis deletion.	Ballabio A	Nature	1990	PMID: 2300168
Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.	Kerem BS	Proceedings of the National Academy of Sciences of the United States of America	1990	PMID: 2236053
The relation between genotype and phenotype in cystic fibrosis--analysis of the most common mutation (delta F508).	Kerem E	The New England journal of medicine	1990	PMID: 2233932
Cystic fibrosis mutations in North American populations of French ancestry: analysis of Quebec French-Canadian and Louisiana Acadian families.	Rozen R	American journal of human genetics	1990	PMID: 2220803
Gradient of distribution in Europe of the major CF mutation and of its associated haplotype. European Working Group on CF Genetics (EWGCFG).	-	Human genetics	1990	PMID: 2210767
Identification of the cystic fibrosis gene: genetic analysis.	Kerem B	Science (New York, N.Y.)	1989	PMID: 2570460
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.	Riordan JR	Science (New York, N.Y.)	1989	PMID: 2475911
http://www.cftr2.org/	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
https://cftr2.org	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1447979749	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1449154729	-	-	-	-
https://www.pharmgkb.org/variant/PA166157525	-	-	-	-
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