ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.2288A>G (p.Tyr763Cys)

gnomAD frequency: 0.00001  dbSNP: rs764459544
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000725121 SCV000334254 pathogenic not provided 2018-08-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000301610 SCV000645493 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2023-11-08 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 763 of the CAPN3 protein (p.Tyr763Cys). This variant is present in population databases (rs764459544, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 16816913, 17236769, 26677118; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 282681). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000725121 SCV002025060 likely pathogenic not provided 2022-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226273 SCV003922484 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2023-03-15 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.2288A>G (p.Tyr763Cys) results in a non-conservative amino acid change located in the Calpain-3, penta-EF-hand domain (IPR029531) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251396 control chromosomes (gnomAD). c.2288A>G has been reported in the literature in multiple individuals affected with limb-girdle muscular dystrophy (example: Pizzanelli_2006, Milic_2007, Saat__2021 and Ganaraja_2021). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003463744 SCV004213783 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2024-03-26 criteria provided, single submitter clinical testing
Natera, Inc. RCV000301610 SCV002085558 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2021-03-12 no assertion criteria provided clinical testing

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