ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 80 of the HSD17B3 protein (p.Arg80Trp). This variant is present in population databases (rs119481077, gnomAD 0.006%). This missense change has been observed in individuals with male pseudohermaphroditism with gynecomastia (PMID: 9758445, 21214500, 22212252, 27899157). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4877). 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 HSD17B3 protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 9758445). This variant disrupts the p.Arg80 amino acid residue in HSD17B3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8075637, 8626842, 12429500, 17551466). 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.