ClinVar Miner

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

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Total submissions: 5
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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 RCV000586469 SCV000696934 likely pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2021-04-09 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 (IPR011527) 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 3.5e-05 in 253874 control chromosomes (gnomAD and publications). c.2936A>C has been reported in the literature in multiple individuals affected with Congenital Bilateral Absence Of The Vas Deferens (CBAVD) who carry the variant in trans with the pathogenic 5T allele (e.g. Dork_1997, Mak_1999, Luo_2021). In addition, the variant was found in two twin siblings with CF who carried another pathogenic mutation (p.R347H) in cis and the common disease variant p.F508del on the other allele (Hojo_1998). It was speculated that the p.D979A variant may contribute to more severe disease in these individuals, however the contributions of the individual variants to the phenotype could not be determined. The variant was also detected in several individuals with pancreatitis, however co-occurred with variants in SPINK1 and PRSS1 (e.g. Zou_2018). At least one publication reports experimental evidence evaluating an impact on protein function, suggesting that the variant results in a partial reduction of CFTR processing and moderate effects on chloride channel dynamics, consistent with the milder CFTR-related phenotype (CBAVD) that has been observed in most patients with the variant (e.g. Clain_2001). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic in association with CBAVD.
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 none provided 2020-02-05 criteria provided, single submitter clinical testing The CFTR c.2936A>C; p.Asp979Ala variant (rs397508462) is reported in the literature in individuals affected with congenital absence of vas deferens who carry a mildly pathogenic variant in CFTR (Dork 1997, Mak 1999, Wilschanski 2006), but is also reported in individuals with pancreatitis who carry variants in other pancreatitis-associated genes (Zou 2018), and in a pair of twins with cystic fibrosis who carry two pathogenic CFTR variants on opposite chromosomes (Hojo 1997). Functional assays show that the p.Asp979Ala variant result in a mild defect (Clain 2001). The p.Asp979Ala variant is reported in the ClinVar database (Variation ID: 53602), and is found in the East Asian 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). While the p.Asp979Ala variant is not predicted to cause classic cystic fibrosis, based on available information, the clinical significance is uncertain for CFTR-related disorders. References: CFTR2 database: Clain J et al. Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function. J Biol Chem. 2001 Mar 23;276(12):9045-9. 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. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999 Jun 16;281(23):2217-24. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006 Oct 1;174(7):787-94. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204.
Invitae RCV000577756 SCV001576737 likely pathogenic Cystic fibrosis 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 979 of the CFTR protein (p.Asp979Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs397508462, ExAC 0.03%). This variant has been observed in combination with another CFTR variant in individuals affected with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 9272157, 10376575). This variant has also been observed in two siblings with severe cystic fibrosis who also carried two CFTR pathogenic variants (PMID: 9493456). ClinVar contains an entry for this variant (Variation ID: 53602). Experimental studies have shown that this missense change affects CFTR protein processing in vitro (PMID: 11118444). This variant disrupts the p.Asp979 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 9401110, 29805046), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577756 SCV000679363 not provided Cystic fibrosis no assertion provided literature only

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