Submissions for variant NM_000197.1(HSD17B3):c.194C>T

gnomAD frequency: 0.00001  dbSNP: rs747329682

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV004555548	SCV005044815	likely pathogenic	Testosterone 17-beta-dehydrogenase deficiency		criteria provided, single submitter	clinical testing	The missense c.194C>T p.Ser65Leu variant in HSD17B3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser65Leu variant has allele frequency 0.001% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Ser65Leu in HSD17B3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 65 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090185	SCV005835104	pathogenic	not provided	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 65 of the HSD17B3 protein (p.Ser65Leu). This variant is present in population databases (rs747329682, gnomAD no frequency). This missense change has been observed in individuals with clinical features of 17-beta-hydroxysteroid dehydrogenase type 3 deficiency (PMID: 8550739, 25326637, 30668521, 32449406, 36154887, 37741351). ClinVar contains an entry for this variant (Variation ID: 242504). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HSD17B3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HSD17B3 function (PMID: 8550739, 37741351). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004555548	SCV005883187	pathogenic	Testosterone 17-beta-dehydrogenase deficiency	2024-12-05	criteria provided, single submitter	clinical testing	Variant summary: HSD17B3 c.194C>T (p.Ser65Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251432 control chromosomes (gnomAD). c.194C>T has been reported in the literature in multiple individuals affected with Testosterone 17-beta-dehydrogenase deficiency (e.g. Andersson_1996, Baxter_2015, Hughes_2019, Zhu_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant inactivated enzyme activity almost completely (Andersson_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8550739, 25383892, 30668521, 36154887). ClinVar contains an entry for this variant (Variation ID: 242504). Based on the evidence outlined above, the variant was classified as pathogenic.