Submissions for variant NM_000070.3(CAPN3):c.1543G>A (p.Gly515Arg)

gnomAD frequency: 0.00034  dbSNP: rs150226817

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000245397	SCV000301870	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724737	SCV000331893	uncertain significance	not provided	2018-08-10	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000245397	SCV000612636	uncertain significance	not specified	2016-12-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692602	SCV000820432	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 515 of the CAPN3 protein (p.Gly515Arg). This variant is present in population databases (rs150226817, gnomAD 0.09%). This missense change has been observed in individual(s) with a progressive myopathy (PMID: 33250842). ClinVar contains an entry for this variant (Variation ID: 254861). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 95%. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000724737	SCV001247172	uncertain significance	not provided	2019-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000724737	SCV002526479	uncertain significance	not provided	2021-12-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33250842)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000245397	SCV002547801	likely benign	not specified	2022-05-27	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1543G>A (p.Gly515Arg) results in a non-conservative amino acid change located in the subdomain III (IPR033883) 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 0.00031 in 150922 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.0011 including 1 homozygote (in the gnomAD database, v3.1 genomes dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0032), allowing no clear conclusions about variant significance. The variant, c.1543G>A, has been reported in the literature in an individual affected with proximal myopathy, who also carried a (likely) pathogenic CAPN3 variant, however the phase of these two variants was not determined (Chakravorty_2020). On the other hand, the variant was also reported in 3 individuals affected with limb-girdle muscular dystrophy (LGMD), however, two of these patients also carried two co-occurring pathogenic variants in other genes, which could explain the phenotype, while the 3rd patient carried a potentially pathogenic CAPN3 variant in cis (LOVD, PMID 30564623). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000724737	SCV003830575	uncertain significance	not provided	2021-11-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000692602	SCV001460837	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-04-17	no assertion criteria provided	clinical testing