ClinVar

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 42 of the CYP11B1 protein (p.Pro42Ser). This variant is present in population databases (rs104894069, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital adrenal hyperplasia (PMID: 9302260). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1179). 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 CYP11B1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CYP11B1 function (PMID: 9302260, 26053152). This variant disrupts the p.Pro42 amino acid residue in CYP11B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26053152; Invitae). 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.