NM_000492.4(CFTR):c.2939T>A (p.Ile980Lys) AND Cystic fibrosis

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Nov 10, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000577032.12

Allele description [Variation Report for NM_000492.4(CFTR):c.2939T>A (p.Ile980Lys)]

NM_000492.4(CFTR):c.2939T>A (p.Ile980Lys)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.2939T>A (p.Ile980Lys)

HGVS:

NC_000007.14:g.117606704T>A
NG_016465.4:g.145921T>A
NM_000492.4:c.2939T>AMANE SELECT
NP_000483.3:p.Ile980Lys
NP_000483.3:p.Ile980Lys
LRG_663t1:c.2939T>A
LRG_663:g.145921T>A
LRG_663p1:p.Ile980Lys
NC_000007.13:g.117246758T>A
NM_000492.3:c.2939T>A

Protein change:

I980K

Links:

dbSNP: rs397508463

NCBI 1000 Genomes Browser:

rs397508463

Molecular consequence:

NM_000492.4:c.2939T>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000679364	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8829643, 20059485
SCV000796476	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Dec 14, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001583667	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 10, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8829643, 8947061, 11101688, 21520337, 28492532
SCV002752446	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely pathogenic (Jul 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?

Dorfman R, Nalpathamkalam T, Taylor C, Gonska T, Keenan K, Yuan XW, Corey M, Tsui LC, Zielenski J, Durie P.

Clin Genet. 2010 May;77(5):464-73. doi: 10.1111/j.1399-0004.2009.01351.x. Epub 2009 Jan 6.

PubMed [citation]

PMID:: 20059485

Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients.

Hubert D, Bienvenu T, Desmazes-Dufeu N, Fajac I, Lacronique J, Matran R, Kaplan JC, Dusser DJ.

Eur Respir J. 1996 Nov;9(11):2207-14.

PubMed [citation]

PMID:: 8947061

See all PubMed Citations (6)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679364.1

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

#	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 Counsyl, SCV000796476.1

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

#	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 Invitae, SCV001583667.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 980 of the CFTR protein (p.Ile980Lys). This variant is present in population databases (rs397508463, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital absence of the vas deferens and/or cystic fibrosis (PMID: 8829643, 8947061, 11101688, 21520337). ClinVar contains an entry for this variant (Variation ID: 53604). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. 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 Ambry Genetics, SCV002752446.1

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

Description

The p.I980K variant (also known as c.2939T>A), located in coding exon 18 of the CFTR gene, results from a T to A substitution at nucleotide position 2939. The isoleucine at codon 980 is replaced by lysine, an amino acid with dissimilar properties. This variant was reported in two individuals, who also had another pathogenic mutation, with congenital bilateral absence of the vas deferens (CBAVD). One individual also had an elevated sweat chloride concentration and presented with chronic sinusitis, nasal polyposis and pancreatic sufficiency (Bienvenu et al. Hum Mutat. 1996;7:182). In another study, this variant was seen in two patients in a cohort of 305 with CBAVD, of which one individual also had p.R117H and the other individual had c.3605delA, however further clinical information was not provided (Steiner et al. Hum Mutat. 2011;32:912-20). In a group of 110 patients who were diagnosed with cystic fibrosis by two abnormal sweat chloride levels and/or two CFTR mutations, one was reported with this variant (Hubert et al. Eur. Respir. J. 1996;9(11):2207-14). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6495 samples (12990 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Mar 16, 2024

ClinVar

Relating variation to medicine