ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1678A>G (p.Thr560Ala)

gnomAD frequency: 0.00004  dbSNP: rs146845466
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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) RCV000279141 SCV000334251 uncertain significance not provided 2015-08-14 criteria provided, single submitter clinical testing
Invitae RCV001859563 SCV002109296 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-08-22 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 560 of the CAPN3 protein (p.Thr560Ala). This variant is present in population databases (rs146845466, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 29970176). ClinVar contains an entry for this variant (Variation ID: 282679). 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: "Tolerated"; 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.
Revvity Omics, Revvity RCV000279141 SCV003828913 uncertain significance not provided 2022-07-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230470 SCV003928549 uncertain significance not specified 2023-04-13 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.1678A>G (p.Thr560Ala) results in a non-conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) 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 2.4e-05 in 251408 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1678A>G has been reported in the literature in at least one compound heterozygous individual affected with Limb-Girdle Muscular Dystrophy (e.g. Fichna_2018). The variant was also found in other heterozygous individuals with suspected/confirmed diagnosis of Limb-Girdle Muscular Dystrophy (e.g. Nallamilli_2018, Meinke_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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