ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.566T>C (p.Leu189Pro)

gnomAD frequency: 0.00002  dbSNP: rs758795961
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000201041 SCV000255668 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2012-12-29 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000729232 SCV000856875 uncertain significance not provided 2017-09-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000201041 SCV003442758 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2021-08-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 189 of the CAPN3 protein (p.Leu189Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 10330340, 11297944, 18055493). ClinVar contains an entry for this variant (Variation ID: 217158). 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.
Revvity Omics, Revvity RCV000729232 SCV003828993 uncertain significance not provided 2020-09-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330573 SCV004039056 uncertain significance not specified 2023-08-02 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.566T>C (p.Leu189Pro) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251456 control chromosomes. c.566T>C has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Groen_2007, Pollitt_2001, Richard_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 publications have been ascertained in the context of this evaluation (PMID: 18055493, 11297944, 10330340).Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV003462350 SCV004213813 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2024-01-25 criteria provided, single submitter clinical testing

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