ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1976C>T (p.Ala659Val)

gnomAD frequency: 0.00001  dbSNP: rs1336908700
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001362439 SCV001558455 uncertain significance Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2022-07-26 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 659 of the CLCN1 protein (p.Ala659Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 10619717). ClinVar contains an entry for this variant (Variation ID: 1054004). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001751713 SCV001986272 uncertain significance not provided 2020-10-16 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10619717)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323870 SCV004028982 uncertain significance not specified 2023-07-21 criteria provided, single submitter clinical testing Variant summary: CLCN1 c.1976C>T (p.Ala659Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 154960 control chromosomes (gnomAD). c.1976C>T has been reported in the literature in at least one homozygous individual affected with Becker's Myotonia congenita (Sasaki_1999). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 10619717). Two ClinVar submitters have assessed this variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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