ClinVar Genomic variation as it relates to human health

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Occurs in three or more cases with a recessive pathogenic variant in the same gene.

Variant summary: CAPN3 c.145C>T (p.Arg49Cys) results in a non-conservative amino acid change in 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 2.4e-05 in 251372 control chromosomes. c.145C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Groen_2007, Charlton_2009, Meinke_2020, Alharbi_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 49 of the CAPN3 protein (p.Arg49Cys). This variant is present in population databases (rs794726871, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 18055493, 18334579, 19285864, 19556129, 28403181). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 193037). 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 95%. This variant disrupts the p.Arg49 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16650086, 17318636, 25135358). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The heterozygous p.Arg49Cys variant in CAPN3 was identified by our study in the compound heterozygous state, with reported VUS variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.002437% (6/246158) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794726871). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg49Cys variant in CAPN3 has been reported in 2 individuals with LGMD (PMID: 18334579, 19285864). Also, the presence of this variant in combination with a reported pathogenic variant and in an individual with LGMD increases the likelihood that the p.Arg49Cys variant is pathogenic (Variation ID: 166790). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This missense variant affects the same residue as the likely pathogenic p.Arg49His variant, raising the possibility that a change at this residue may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg49Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PM5, PP3 (Richards 2015).