ClinVar

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 276 of the CLCN1 protein (p.Gly276Ser). This variant is present in population databases (rs765181341, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of autosomal recessive myotonia congenita (PMID: 24037712, 32117024; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447072). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly276 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 17932099), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.