ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2939T>A (p.Ile980Lys) (rs397508463)

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Total submissions: 6
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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 2017-02-01 criteria provided, single submitter clinical testing Variant summary: The CFTR c.2939T>A (p.Ile980Lys) variant involves the alteration of a conserved nucleotide located in the ABC transporter type 1, transmembrane domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/121870 control chromosomes at a frequency of 0.0000164, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in at least 5 CBAVD patients in the literature, in each patient a second pathogenic variant has been reported. The variant has not been reported with a classification provided from databases or repuable clinical labs. Taken together, this variant is classified as a likely pathogenic variant.
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 disorders 2018-01-29 criteria provided, single submitter curation
Invitae RCV000577032 SCV001583667 pathogenic Cystic fibrosis 2020-06-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with lysine at codon 980 of the CFTR protein (p.Ile980Lys). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and lysine. This variant is present in population databases (rs397508463, ExAC 0.009%). This variant has been observed in combination with another CFTR variant in individuals affected with cystic fibrosis (PMID: 8947061) or congenital absence of the vas deferens (PMID: 8829643, 8947061, 11101688, 21520337). ClinVar contains an entry for this variant (Variation ID: 53604). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577032 SCV000679364 not provided Cystic fibrosis no assertion provided literature only

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