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

gnomAD frequency: 0.00003  dbSNP: rs397508463

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586046	SCV000696937	likely pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation	2023-07-12	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2939T>A (p.Ile980Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 251838 control chromosomes. c.2939T>A has been reported in the literature in individuals affected with features of Congenital Bilateral Absence Of The Vas Deferens and/or Cystic Fibrosis/CFTR-related disorders (example, Bienvenu_1997, Claustres_2000, Hubert_1996, Jezequel_2000, Steiner_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8829643, 10923036, 20059485, 9272157, 8947061, 11101688, 21520337). Six submitters inclusing the CFTR-France database have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (LP, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl	RCV000577032	SCV000796476	uncertain significance	Cystic fibrosis	2017-12-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001213	SCV001158374	uncertain significance	not specified	2019-04-17	criteria provided, single submitter	clinical testing	The CFTR c.2939T>A; p.Ile980Lys variant (rs397508463) is reported in the literature in multiple individuals affected with congenital absence of the vas deferens (CBAVD) or cystic fibrosis (CF) (Bienvenu 1996, Hubert 1996, Jezequel 2000, Steiner 2011). In all affected individuals carrying this variant, a second pathogenic variant was also identified (Bienvenu 1996, Hubert 1996, Jezequel 2000, Steiner 2011). The p.Ile980Lys variant is present on only two chromosomes (2/251150 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 980 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Despite its prevalence in affected individuals, due to limited information, the significance of the p.Ile980Lys variant is uncertain at this time. References: Bienvenu T et al. A novel missense mutation in exon 16 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified in CBAVD patients. Hum Mutat. 1996;7(2):182. Hubert D et al. Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients. Eur Respir J. 1996 Nov;9(11):2207-14. Jezequel P et al. Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations. Mol Hum Reprod. 2000 Dec;6(12):1063-7. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20.
CFTR-France	RCV001009475	SCV001169570	pathogenic	CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation
Invitae	RCV000577032	SCV001583667	pathogenic	Cystic fibrosis	2023-11-10	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000577032	SCV002752446	likely pathogenic	Cystic fibrosis	2023-10-27	criteria provided, single submitter	clinical testing	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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Revvity Omics, Revvity	RCV003137585	SCV003826246	likely pathogenic	not provided	2021-11-19	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577032	SCV000679364	not provided	Cystic fibrosis		no assertion provided	literature only