Submissions for variant NM_000197.2(HSD17B3):c.614T>A (p.Val205Glu)

gnomAD frequency: 0.00004  dbSNP: rs372027264

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001821705	SCV002067491	likely pathogenic	not provided	2020-06-19	criteria provided, single submitter	clinical testing	The sequence change, c.614T>A, in exon 9 that results in an amino acid change, p.Val205Glu. The p.Val205Glu change affects a moderately conserved amino acid residue located in a domain of the HSD17B3 protein that is known to be functional. The p.Val205Glu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).This particular amino acid change has been described in patients with 17 Beta-hydroxysteroid dehydrogenase 3 in both homozygous and compound heterozygous state (PMIDs: 30668521, 25740850). Experimental studies showed loss of enzymatic activity for the mutant cDNA expressed in the transfected cells (PMID: 8550739). This sequence change has been described in the gnomAD database with a low population frequency of 0.0062% the non-Finnish European subpopulation (dbSNP rs372027264). These collective evidences indicate that this sequence change is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001821705	SCV003441354	likely pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 205 of the HSD17B3 protein (p.Val205Glu). This variant is present in population databases (rs372027264, gnomAD 0.006%). This missense change has been observed in individual(s) with 17-beta hydroxysteroid dehydrogenase 3 deficiency (PMID: 24025597, 25740850; Invitae). 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: 492767). 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 HSD17B3 protein function. Experimental studies have shown that this missense change affects HSD17B3 function (PMID: 8550739). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767420	SCV005381264	pathogenic	Testosterone 17-beta-dehydrogenase deficiency	2024-08-28	criteria provided, single submitter	clinical testing	Variant summary: HSD17B3 c.614T>A (p.Val205Glu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251478 control chromosomes, predominantly at a frequency of 6.2e-05 within the Non-Finnish European subpopulation in the gnomAD database. c.614T>A has been reported in the literature in individuals affected with Testosterone 17-beta-dehydrogenase deficiency (Andersson_1996, Chuang_2013, Lee_2007, Phelan_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in almost diminished enzyme activity in vitro (Andersson_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8550739, 24025597, 17466011, 25740850). ClinVar contains an entry for this variant (Variation ID: 492767). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000582417	SCV000692124	pathogenic	Pseudohermaphroditism	2011-10-25	no assertion criteria provided	clinical testing