NM_000492.4(CFTR):c.3067_3072del (p.Ile1023_Val1024del) AND Cystic fibrosis

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Sep 24, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000046775.31

Allele description [Variation Report for NM_000492.4(CFTR):c.3067_3072del (p.Ile1023_Val1024del)]

NM_000492.4(CFTR):c.3067_3072del (p.Ile1023_Val1024del)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674472:DNase I hypersensitive sites in introns 16 and 17a of CFTR [Gene]

Variant type:

Deletion

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.3067_3072del (p.Ile1023_Val1024del)

Other names:

CFTR, 3199del6

HGVS:

NC_000007.13:g.117250647_117250652del
NC_000007.14:g.117610597_117610602del
NG_016465.4:g.149814_149819del
NG_056128.2:g.3651_3656del
NM_000492.4:c.3067_3072delMANE SELECT
NP_000483.3:p.Ile1023_Val1024del
NP_000483.3:p.Ile1023_Val1024del
NP_000483.3:p.Ile1023_Val1024del
LRG_663t1:c.3067_3072del
LRG_663:g.149814_149819del
LRG_663p1:p.Ile1023_Val1024del
NC_000007.13:g.117250647_117250652del
NC_000007.13:g.117250651_117250656del
NC_000007.13:g.117250651_117250656delATAGTG
NG_016465.1:g.135635_135640del
NM_000492.3:c.3063_3068delAGTGAT
NM_000492.3:c.3067_3072del
NM_000492.3:c.3067_3072delATAGTG

Links:

dbSNP: rs121908767

NCBI 1000 Genomes Browser:

rs121908767

Molecular consequence:

NM_000492.4:c.3067_3072del - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000074788	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 3, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7516234, 12394343, 15287992, 22020151, 22627569, 28492532
SCV000696944	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 18, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22627569, 15287992, 26146130, 15371903, 26708955, 15371902, 15371907, 12394343 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000886159	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (Nov 5, 2018)	unknown	clinical testing	Citation Link,
SCV001169285	CFTR-France	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	Pathogenic (Jan 29, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV001193959	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 4, 2019)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 15371908, 10798368, 12172395, 15371907, 11668613, 8707304, 15371903, 15017334, 15638824, 7516234, 22020151, 18456578, 12394343, 21679131 Citation Link,
SCV001425301	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27738188, 25741868
SCV001981576	CFTR2	reviewed by expert panel (Submitter's publication and website)	Pathogenic (Sep 24, 2021)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002574073	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2022)	unknown	curation	PubMed (1) [See all records that cite this PMID]
SCV002753642	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jan 11, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15371908, 15698946, 15775760, 7516234 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	4	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research, curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Report on the p.Ser489X (p.Ser489*) CFTR mutation, a variant with severe associated phenotype and high prevalence in a Quebec French-Canadian cystic fibrosis patient population.

De Bie I, Agatep R, Scott P, Ruchon A.

Genet Med. 2012 Oct;14(10):883-6. doi: 10.1038/gim.2012.57. Epub 2012 May 24.

PubMed [citation]

PMID:: 22627569

See all PubMed Citations (26)

Details of each submission

From Invitae, SCV000074788.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant, c.3067_3072del, results in the deletion of 2 amino acid(s) of the CFTR protein (p.Ile1023_Val1024del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397508492, gnomAD 0.01%). This variant has been observed in individual(s) with cystic fibrosis or congenital absence of the vas deferens (PMID: 7516234, 12394343, 15287992, 22020151, 22627569). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 3199del6 or 3195del6. ClinVar contains an entry for this variant (Variation ID: 38480). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696944.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: The c.3067_3072delATAGTG (a.k.a. 3199del6) in CFTR gene is an in-frame deletion that expected to remove Ile1023 and Val1024 from the CFTR protein. Mutation Taster predicts deleterious outcome. The variant is absent from the large and broad cohorts of the ExAC project. The variant of interest has been identified in multiple affected individuals presented with CF and was referred as causative mutation in peer-reviewed publications. At least one reputable clinical laboratory/diagnostic center classified the variant as Pathogenic. Taking together, the variant was classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV000886159.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR-France, SCV001169285.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193959.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

NM_000492.3(CFTR):c.3067_3072del6(aka 3199del6) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 15371908, 10798368, 12172395, 15371907, 11668613, 8707304, 15371903, 15017334, 15638824, 7516234, 22020151, 18456578, 12394343 and 21679131. Classification of NM_000492.3(CFTR):c.3067_3072del6(aka 3199del6) 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV001425301.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

c.3067_3072del has been observed in multiple patients presenting with cystic fibrosis in whom a second disease-associated variant was identified. This variant (rs397508492) is rare (<0.1%) in a large population dataset (gnomAD: 7/251080 total alleles; 0.002788%; no homozygotes). Additionally, seven submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. We consider this variant to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR2, SCV001981576.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002574073.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	curation	PubMed (1)

Description

This variant was identified in 4 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3_VSTR, PM4, PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Ambry Genetics, SCV002753642.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.3067_3072delATAGTG pathogenic mutation (also known as 3199del6, 3195del6, and p.I1023_V1024del) is located in coding exon 19 of the CFTR gene. This pathogenic mutation results from an in-frame deletion of 6 nucleotides at positions 3067 to 3072. This results in the deletion of an isoleucine and a valine residue between codons 1023 and 1024. This mutation was first reported in an individual with cystic fibrosis (CF) in trans with a frameshift alteration (Claustres M et al. Hum. Mol. Genet., 1994 Feb;3:371). In another study, this mutation was identified in trans with a nonsense alteration in an individual with CF with meconium ileus, pulmonary symptoms, pancreatic sufficiency, and elevated sweat chloride levels (Buyse IM et al. Genet. Med.;6:426-30). In a cohort of unrelated French Canadian individuals with CF, 21 of 22 individuals bearing this mutation and another severe CFTR alteration were pancreatic insufficient (Ruchon AF et al. Genet. Med., 2005 Mar;7:210-1). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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