ClinVar

Description

This missense change has been observed in individual(s) with clinical features of familial hypothyroidism (PMID: 16756469, 21707688, 24895636, 26709262). 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg519 amino acid residue in TSHR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16756469). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TSHR function (PMID: 16756469). 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 TSHR protein function. This variant is present in population databases (rs756016910, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 519 of the TSHR protein (p.Arg519Cys).