ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1699G>T (p.Gly567Trp)

dbSNP: rs727503839
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000790649 SCV000225748 pathogenic not provided 2017-02-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000174442 SCV000645478 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2024-08-02 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 567 of the CAPN3 protein (p.Gly567Trp). This variant is present in population databases (rs727503839, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy type 2A (PMID: 9150160, 10330340, 26404900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 166791). 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 expected to disrupt CAPN3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000790649 SCV001247174 pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000790649 SCV002018053 pathogenic not provided 2023-05-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003114302 SCV003801335 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2023-01-04 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.1699G>T (p.Gly567Trp) results in a non-conservative amino acid change located in peptidase C2, calpain, large subunit, domain III (IPR022682) 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 4e-06 in 251382 control chromosomes (gnomAD). c.1699G>T has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with (suspected) Limb-Girdle Muscular Dystrophy (e.g., Richard_1997, Magri_2015, Nallamilli_2018, Barp_2020). These data indicate that the variant is very likely to be associated with disease. A publication reported experimental evidence, demonstrating the lack of calpain activity in a cell line homozygous for the variant (Cerino_2020). Five ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences RCV004532716 SCV004120714 pathogenic CAPN3-related disorder 2023-01-27 criteria provided, single submitter clinical testing The CAPN3 c.1699G>T variant is predicted to result in the amino acid substitution p.Gly567Trp. This variant has been reported in the homozygous and compound heterozygous state in many individuals with autosomal recessive CAPN3-related disorders (Richard et al 1997. PubMed ID: 9150160; Additional File 1 in Magri. 2015. PubMed ID: 26404900; Supp. Table 1 Barp et al. 2020. PubMed ID: 31555977; http://www.lovd.nl/CAPN3). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-42695154-G-T). This variant is interpreted as pathogenic.
Baylor Genetics RCV003474805 SCV004211573 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2024-03-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000174442 SCV002085534 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-07-02 no assertion criteria provided clinical testing

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