ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 861 of the SLC12A3 protein (p.Arg861His). This variant is present in population databases (rs751929135, gnomAD 0.003%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 17873326, 31363482, 33348466). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg852His. ClinVar contains an entry for this variant (Variation ID: 1458237). 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 SLC12A3 protein function. This variant disrupts the p.Arg861 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21415153, 23328711, 27582097, 27872838). 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.