ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 357 of the CYP21A2 protein (p.Arg357Gln). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with classic salt wasting as well as simple virilizing forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 9099839, 9187661, 26804566). 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 R356Q. ClinVar contains an entry for this variant (Variation ID: 1675315). 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 CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 9187661). This variant disrupts the p.Arg357 amino acid residue in CYP21A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9099839, 9187661, 26804566). 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.