ClinVar Genomic variation as it relates to human health

Variant summary: SGCA c.269A>G (p.Tyr90Cys) results in a non-conservative amino acid change located in the Dystroglycan-type cadherin-like domain (IPR006644) 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 8e-06 in 249164 control chromosomes (gnomAD). c.269A>G has been reported in the literature in two homozygous individuals from the same family, who were affected with Limb-Girdle Muscular Dystrophy (Moreira_2003). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated the complete lack of the protein at the cell surface, while the variant protein was visible intracellularly when immunostaining is performed on permeabilized cells (Soheili_2012). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 90 of the SGCA protein (p.Tyr90Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with sarcoglycanopathy (PMID: 12566530). ClinVar contains an entry for this variant (Variation ID: 2429327). 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%. Experimental studies have shown that this missense change affects SGCA function (PMID: 22095924). 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.

Published functional studies demonstrate that this variant leads to loss of protein function (PMID: 22095924); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19781108, 24742800, 12566530, 22095924)