ClinVar

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 292 of the CYP21A2 protein (p.Gly292Ser). 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 salt-wasting and simple virilizing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 9497336, 26206692, 34821488). 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: 12156). 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: 9497336, 28539365). This variant disrupts the p.Gly292 amino acid residue in CYP21A2. Other variant(s) that disrupt this residue have been observed in individuals with CYP21A2-related conditions (PMID: 10364682, 12915679), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.