ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.608C>T (p.Ala203Val)

gnomAD frequency: 0.00001  dbSNP: rs763719290
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000314946 SCV000344161 uncertain significance not provided 2016-07-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000686362 SCV000813878 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-02-10 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 203 of the CAPN3 protein (p.Ala203Val). This variant is present in population databases (rs763719290, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 289751). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV001267485 SCV001445666 uncertain significance Inborn genetic diseases 2019-06-18 criteria provided, single submitter clinical testing
3billion RCV000686362 SCV003841629 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2024-07-30 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.92 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with CAPN3-related disorder (PMID: 35169782 / 3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 35169782 / 3billion dataset). A different missense change at the same codon (p.Ala203Gly) has been reported to be associated with CAPN3-related disorder (ClinVar ID: VCV000843051). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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