ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 145 of the SRD5A2 protein (p.Arg145Trp). This variant is present in population databases (rs759561106, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of steroid-5 alpha-reductase deficiency (PMID: 8262007, 16181229, 32713132, 35700942). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 not expected to disrupt SRD5A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SRD5A2 function (PMID: 8110760, 32380235). This variant disrupts the p.Arg145 amino acid residue in SRD5A2. Other variant(s) that disrupt this residue have been observed in individuals with SRD5A2-related conditions (PMID: 25899528), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.