VCV000035822.56 - ClinVar

NM_000492.4(CFTR):c.1397C>G (p.Ser466Ter)

Germline

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.

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.[1397C>G;3209G>A]

Identifiers

NM_000492.4(CFTR):c.1397C>G (p.Ser466Ter)

Variation ID: 35822 Accession: VCV000035822.56

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117559468 (GRCh38) [ NCBI UCSC ] 7: 117199522 (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	Mar 24, 2015	Apr 4, 2026	Mar 17, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1397C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Ser466Ter	nonsense
NC_000007.14:g.117559468C>G
NC_000007.13:g.117199522C>G
NG_016465.4:g.98685C>G
LRG_663:g.98685C>G
LRG_663t1:c.1397C>G	LRG_663p1:p.Ser466Ter

... more HGVS ... less HGVS

Protein change

S466*

Other names

Canonical SPDI

NC_000007.14:117559467:C:G

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.

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

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA342833 dbSNP: rs121908805 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	3863	6322
CFTR-AS1	-	-	-	GRCh38	-	624

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 (12)	reviewed by expert panel	Mar 17, 2017	RCV000029475.38
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 22, 2023	RCV000724154.37
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	-	RCV001004451.8
CFTR-related disorder	Pathogenic (3)	criteria provided, single submitter	Nov 26, 2025	RCV001826510.13
Obstructive azoospermia	Pathogenic (1)	criteria provided, single submitter	Aug 23, 2021	RCV001642234.9
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Mar 4, 2024	RCV003473124.2
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	Jun 7, 2024	RCV005042089.1

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 17, 2017) C Contributing to aggregate classification	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Cystic fibrosis	CFTR2 Study: CFTR2 Accession: SCV000087507.4 First in ClinVar: Oct 18, 2013 Last updated: Jan 06, 2018	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

Pathogenic (Nov 03, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848804.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: show The c.1397C>G (p.Ser466X) variant in CFTR has been reported in at least 14 individuals with cystic fibrosis, and was found in the heterozygous state with the CFTR p.Phe508del variant in at least 3 cases (Deufel 1994 PMID: 7509683, Sahami 2014 PMID: 24696795, Petrova 2020 PMID: 32429104, Claustres 2017 PMID: 28603918). It has also been identified in 0.0072% (3/41412) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID 35822). This nonsense variant leads to a premature termination codon at position 466, which is predicted to lead to a truncated or absent protein. Loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_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 (Aug 20, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cystic fibrosis	Ambry Genetics Accession: SCV002702254.3 First in ClinVar: Nov 29, 2022 Last updated: Jan 13, 2025	Publications: PubMed (2) PubMed: 17662673‚ 7509683 Comment: show The p.S466* pathogenic mutation (also known as c.1397C>G), located in coding exon 11 of the CFTR gene, results from a C to G substitution at nucleotide position 1397. This changes the amino acid from a serine to a stop codon within coding exon 11. This mutation was described in two unrelated German individuals with pancreatic insufficient cystic fibrosis (CF) in conjunction with p.F508del (Deufel A et al. Hum. Mutat., 1994;3:64-6). This mutation was also detected in the homozygous state in four unrelated Iranian individuals with CF (Alibakhshi R et al. J. Cyst. Fibros., 2008 Mar;7:102-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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 (Oct 01, 2022) 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: SCV002821844.24 First in ClinVar: Jan 21, 2023 Last updated: Jan 11, 2026	Comment: show CFTR: PVS1, PM2, PP4:Moderate, PM3: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: 1

Pathogenic (Jul 24, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	not provided	Blueprint Genetics Accession: SCV000927818.1 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: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Mar 14, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Cystic fibrosis	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052125.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 10, 2019	Publications: PubMed (3) PubMed: 23974870‚ 24696795‚ 7509683 Comment: show Variant summary: CFTR c.1397C>G (p.Ser466X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.1477C>T, p.Gln493X; c.1573C>T, p.Gln525X; c.1624G>T, p.Gly542X). The variant allele was found at a frequency of 1.8e-05 in 276952 control chromosomes (gnomAD). This variant has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Deufel_1994, Sosnay_2013, Sahami_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 (-) 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: SCV001163496.1 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 (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: SCV001169481.1 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 (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: SCV001860338.1 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: 1

Pathogenic (Aug 29, 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: SCV002507336.1 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 (Nov 05, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Cystic fibrosis	Mendelics Accession: SCV000886194.2 First in ClinVar: Dec 15, 2018 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 (Feb 22, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004221658.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (15) PubMed: 15365999‚ 15727251‚ 17627383‚ 17662673‚ 18951463‚ 21198395‚ 21296036‚ 23974870‚ 24106596‚ 24586523‚ 24696795‚ 31036917‚ 31589614‚ 32429104‚ 7509683 Comment: show This nonsense variant causes the premature termination of CFTR protein synthesis. The frequency of this variant in the general population, 0.00012 (3/24954 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Cystic Fibrosis (PMID: 32429104 (2020), 24696795 (2014), 24586523 (2014), 24106596 (2013), 21296036 (2011), 18951463 (2008)). 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 (Mar 04, 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: SCV004213427.2 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 (Jun 07, 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: SCV005673320.1 First in ClinVar: Jan 25, 2025 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 (Feb 24, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000700723.3 First in ClinVar: Jan 06, 2018 Last updated: Apr 13, 2025	Other databases http://genet.sickkids.on.ca/cftr… http://genet.sickkids.on.ca/cftr/app http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=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: 1 Zygosity: 1 Single Heterozygote Sex: mixed

Pathogenic (Jul 15, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	MGZ Medical Genetics Center Accession: SCV002579918.2 First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025 Comment: ACMG criteria applied: PVS1, PS4_MOD, PM3, PM2_SUP	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 Sex: female

Pathogenic (Jul 11, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV006557399.1 First in ClinVar: Oct 18, 2025 Last updated: Oct 18, 2025	Comment: show Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. (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 (Nov 26, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	CFTR-related disorders	Natera, Inc. Accession: SCV002080589.2 First in ClinVar: Feb 13, 2022 Last updated: Apr 04, 2026	Publications: PubMed (3) PubMed: 17662673‚ 35110256‚ 38744777 Comment: show The c.1397C>G variant in CFTR is a nonsense variant predicted to introduce a stop codon at amino acid 466. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 17662673, 35110256, 38744777). Given the available evidence, this variant is 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 (May 03, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV001251842.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	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 (Feb 22, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cystic fibrosis	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001584838.6 First in ClinVar: May 10, 2021 Last updated: Feb 15, 2026	Publications: PubMed (12) PubMed: 16436643‚ 1695717‚ 17662673‚ 21198395‚ 23974870‚ 24106596‚ 24586523‚ 24696795‚ 25910067‚ 7509683‚ 7691345‚ 9725922 Comment: show This sequence change creates a premature translational stop signal (p.Ser466*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs121908805, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis. While this variant is commonly found in cis with p.Arg1070Gln, it has also been observed without p.Arg1070Gln in affected individuals and is expected to be causative for CFTR-related conditions whether p.Arg1070Gln is present or not (PMID: 7509683, 16436643, 17662673, 21198395, 23974870, 24106596, 24586523, 24696795, 25910067). This variant is also known as 1529C>G. ClinVar contains an entry for this variant (Variation ID: 35822). 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 (Feb 23, 2026) 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: SCV002574116.2 First in ClinVar: Sep 24, 2022 Last updated: Apr 04, 2026	Comment: show Criteria applied: PVS1,PS1,PM3_STR,PM2_SUP,PP4 (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) Sex: female

Pathogenic (Aug 29, 2019) N Not contributing to aggregate classification	no assertion criteria provided	CFTR-related disorders	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002507420.1 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 (Sep 05, 2024) N Not contributing to aggregate classification	no assertion criteria provided	CFTR-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV005362558.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: show The CFTR c.1397C>G variant is predicted to result in premature protein termination (p.Ser466*). This variant has been reported to be causative for cystic fibrosis in the presence of a second pathogenic variant (see example: Table S2, Sosnay et al. 2013. PubMed ID: 23974870; Petrova et al. 2020. PubMed ID: 32429104; Chernykh et al. 2023. PubMed ID: 38003474). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted 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

Comment:

The c.1397C>G (p.Ser466X) variant in CFTR has been reported in at least 14 individuals with cystic fibrosis, and was found in the heterozygous state with the CFTR p.Phe508del variant in at least 3 cases (Deufel 1994 PMID: 7509683, Sahami 2014 PMID: 24696795, Petrova 2020 PMID: 32429104, Claustres 2017 PMID: 28603918). It has also been identified in 0.0072% (3/41412) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID 35822). This nonsense variant leads to a premature termination codon at position 466, which is predicted to lead to a truncated or absent protein. Loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting.

Comment:

The p.S466* pathogenic mutation (also known as c.1397C>G), located in coding exon 11 of the CFTR gene, results from a C to G substitution at nucleotide position 1397. This changes the amino acid from a serine to a stop codon within coding exon 11. This mutation was described in two unrelated German individuals with pancreatic insufficient cystic fibrosis (CF) in conjunction with p.F508del (Deufel A et al. Hum. Mutat., 1994;3:64-6). This mutation was also detected in the homozygous state in four unrelated Iranian individuals with CF (Alibakhshi R et al. J. Cyst. Fibros., 2008 Mar;7:102-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

Variant summary: CFTR c.1397C>G (p.Ser466X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.1477C>T, p.Gln493X; c.1573C>T, p.Gln525X; c.1624G>T, p.Gly542X). The variant allele was found at a frequency of 1.8e-05 in 276952 control chromosomes (gnomAD). This variant has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Deufel_1994, Sosnay_2013, Sahami_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This nonsense variant causes the premature termination of CFTR protein synthesis. The frequency of this variant in the general population, 0.00012 (3/24954 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Cystic Fibrosis (PMID: 32429104 (2020), 24696795 (2014), 24586523 (2014), 24106596 (2013), 21296036 (2011), 18951463 (2008)). Based on the available information, this variant is classified as pathogenic.

Comment:

The c.1397C>G variant in CFTR is a nonsense variant predicted to introduce a stop codon at amino acid 466. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 17662673, 35110256, 38744777). Given the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ser466*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs121908805, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis. While this variant is commonly found in cis with p.Arg1070Gln, it has also been observed without p.Arg1070Gln in affected individuals and is expected to be causative for CFTR-related conditions whether p.Arg1070Gln is present or not (PMID: 7509683, 16436643, 17662673, 21198395, 23974870, 24106596, 24586523, 24696795, 25910067). This variant is also known as 1529C>G. ClinVar contains an entry for this variant (Variation ID: 35822). For these reasons, this variant has been classified as Pathogenic.

Comment:

The CFTR c.1397C>G variant is predicted to result in premature protein termination (p.Ser466*). This variant has been reported to be causative for cystic fibrosis in the presence of a second pathogenic variant (see example: Table S2, Sosnay et al. 2013. PubMed ID: 23974870; Petrova et al. 2020. PubMed ID: 32429104; Chernykh et al. 2023. PubMed ID: 38003474). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Distribution of pathogenic variants in the CFTR gene in a representative cohort of people with cystic fibrosis in the Kingdom of Bahrain.	Majed OAK	Molecular genetics and genomics : MGG	2024	PMID: 38744777
Association Between Cystic Fibrosis Severity Markers and CFTR Genotypes in Turkish Children.	Başaran AE	Turkish thoracic journal	2021	PMID: 35110256
Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.	Petrova NV	Genes	2020	PMID: 32429104
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
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
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
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
CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients.	Ziętkiewicz E	PloS one	2014	PMID: 24586523
Analysis of CFTR Gene Mutations in Children with Cystic Fibrosis, First Report from North-East of Iran.	Mehdizadeh Hakkak A	Iranian journal of basic medical sciences	2013	PMID: 24106596
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis.	Ivady G	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2011	PMID: 21296036
Spectrum of CFTR gene mutations in Iranian Azeri Turkish patients with cystic fibrosis.	Bonyadi M	Genetic testing and molecular biomarkers	2011	PMID: 21198395
Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships.	Krasnov KV	Human mutation	2008	PMID: 18951463
Analysis of the CFTR gene in Iranian cystic fibrosis patients: identification of eight novel mutations.	Alibakhshi R	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 17662673
Analysis of cystic fibrosis gene mutations and associated haplotypes in the Croatian population.	Knezević J	Genetic testing	2007	PMID: 17627383
A haplotype framework for cystic fibrosis mutations in Iran.	Elahi E	The Journal of molecular diagnostics : JMD	2006	PMID: 16436643
Spectrum of cystic fibrosis mutations in Serbia and Montenegro and strategy for prenatal diagnosis.	Radivojevic D	Genetic testing	2004	PMID: 15727251
Identification of novel and rare mutations in California Hispanic and African American cystic fibrosis patients.	Alper OM	Human mutation	2004	PMID: 15365999
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.	Cohn JA	The New England journal of medicine	1998	PMID: 9725922
Three novel mutations (I506S, S466X, 1651A-->T) in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) detected in patients of southern German descent.	Deufel A	Human mutation	1994	PMID: 7509683
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.	Yang Y	Human molecular genetics	1993	PMID: 7691345
A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.	Cutting GR	Nature	1990	PMID: 1695717
http://genet.sickkids.on.ca/cftr/app	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
https://cftr2.org	-	-	-	-
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Text-mined citations for rs121908805 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 04, 2026