ClinVar Genomic variation as it relates to human health

The R221C variant in the SGCA gene has been reported previously in the compound heterozygous state, with a second SGCA missense variant, in a Chinese individual with childhood-onset muscle weakness, myalgia, cardiac abnormalities, and elevated creatine kinase (Yu et al., 2017). The R221C variant is observed in 9/30,778 (0.029%) alleles from individuals of South Asian background, in large population cohorts (Lek et al., 2016). The R221C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R221C as a variant of uncertain significance.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 221 of the SGCA protein (p.Arg221Cys). This variant is present in population databases (rs748936034, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 28403181, 32528171; Invitae). 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: 452720). 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 SGCA protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Variant summary: SGCA c.661C>T (p.Arg221Cys) results in a non-conservative amino acid change located in the Sarcoglycan alpha/epsilon second domain (IPR048347) 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 6e-05 in 251336 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SGCA causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (6e-05 vs 0.002), allowing no conclusion about variant significance. c.661C>T has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Stranneheim_2021, Bardhan_2022, Ek_2023). 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: 28403181, 30764848, 32528171, 33726816, 37273706, 32875335, 35416532). ClinVar contains an entry for this variant (Variation ID: 452720). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.