ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 299 of the GLRA1 protein (p.Arg299Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hyperekplexia (PMID: 8298642; Invitae). This variant is also known as p.Arg271Leu. ClinVar contains an entry for this variant (Variation ID: 16060). 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) has been performed at Invitae 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 GLRA1 protein function. Experimental studies have shown that this missense change affects GLRA1 function (PMID: 7518444). This variant disrupts the p.Arg299 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8298642, 8733061, 19073849, 28122427, 28138086). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.