ClinVar Genomic variation as it relates to human health

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)

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.

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 variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 254861). 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. 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.