ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2936A>C (p.Asp979Ala) (rs397508462)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586469 SCV000696934 likely pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2019-01-07 criteria provided, single submitter clinical testing Variant summary: CFTR c.2936A>C (p.Asp979Ala) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 246182 control chromosomes (gnomAD and publications). The variant, c.2936A>C, had been detected in at least two Congenital Bilateral Absence of the Vas Deferens (CBAVD) patients with another pathogenic variant (5T allele) in trans (Dork_1997, Mak_1999). The variant was also detected, and assumed to have a worsening effect, in two siblings with severe CF, together with a CF-causing mutation (p.R347H) in cis that was inherited from a healthy mother and p.F508del in the other allele inherited from a healthy father (Hojo_1998). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant was shown to have a mild residual activity in isolation, which is consistent with the mild CFTR-related phenotype that has been observed (i.e. CBAVD (Clain_2001)). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000577756 SCV000800040 uncertain significance Cystic fibrosis 2018-05-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001126 SCV001158266 uncertain significance not specified 2019-03-15 criteria provided, single submitter clinical testing The CFTR c.2936A>C; p.Asp979Ala variant (rs397508462) is reported in the literature in an individual with congenital absence of vas deferens who carried the mild 5T allele on the opposite chromosome (Dork 1997). However, this variant has been reported in cis with a moderately pathogenic variant (Arg347His) in a pair of twins with cystic fibrosis who carry F508del on the opposite chromosome (Hojo 1997). The p.Asp979Ala variant is reported in the ClinVar database (Variation ID: 53602). It is found in the East Asian general population with an allele frequency of 0.05% (9/18394 alleles) in the Genome Aggregation Database. The asparagine at codon 979 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. A different variant at this codon, p.Asp979Val, is reported as a CF-causing variant in the CFTR2 database (see CFTR2 database link). However, due to limited information, the clinical significance of the p.Asp979Ala variant is uncertain at this time. REFERENCES CFTR2 database: Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 Sep;100(3-4):365-77. Hojo S et al. (Two cases of cystic fibrosis in Japanese/German twins). Nihon Kyobu Shikkan Gakkai Zasshi. 1997 Nov;35(11):1259-64.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577756 SCV000679363 not provided Cystic fibrosis no assertion provided literature only

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