ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.2236G>A (p.Glu746Lys)

gnomAD frequency: 0.00003  dbSNP: rs752155690
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000176144 SCV000227752 uncertain significance not provided 2016-06-07 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001117732 SCV001275952 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001117732 SCV001414783 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 746 of the CAPN3 protein (p.Glu746Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs752155690, ExAC 0.01%). 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: 195554). 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 disruptive. 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 RCV000176144 SCV001993885 uncertain significance not provided 2019-05-15 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc. RCV001117732 SCV002085557 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2019-10-28 no assertion criteria provided clinical testing

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