Submissions for variant NM_000197.2(HSD17B3):c.845C>T (p.Pro282Leu)

gnomAD frequency: 0.00005  dbSNP: rs144809928

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255975	SCV000322434	pathogenic	not provided	2016-05-05	criteria provided, single submitter	clinical testing	The P282L pathogenic variant in the HSD17B3 gene has been reported previously in association with 17-beta hydroxysteroid dehydrogenase 3 deficiency in multiple individuals in the heterozygous state in the presence of a second HSD17B3 variant (Andersson et al., 1996; Boehmer et al., 1999; Phelan et al., 2015). Additionally, functional studies in transfected 239 cells with the P282L variant show that this variant inactivates the enzyme (Andersson et al., 1996). The P282L variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. The P282L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P282L as a pathogenic variant.
Ambry Genetics	RCV001267038	SCV001445219	pathogenic	Inborn genetic diseases	2019-09-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255975	SCV004296021	likely pathogenic	not provided	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 282 of the HSD17B3 protein (p.Pro282Leu). This variant is present in population databases (rs144809928, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive 17-beta hydroxysteroid dehydrogenase 3 deficiency (PMID: 8550739, 10599740, 25740850). ClinVar contains an entry for this variant (Variation ID: 265484). 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	RCV004701359	SCV005204374	likely pathogenic	Testosterone 17-beta-dehydrogenase deficiency	2024-06-26	criteria provided, single submitter	clinical testing	Variant summary: HSD17B3 c.845C>T (p.Pro282Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250756 control chromosomes. c.845C>T has been reported in the literature in compound heterozygous individuals affected with Testosterone 17-beta-dehydrogenase deficiency (Andersson_1996, Boehmer_1999, Phelan_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in an in vitro assay (Andersson_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8550739, 10599740, 25740850). ClinVar contains an entry for this variant (Variation ID: 265484). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583165	SCV000692125	pathogenic	Pseudohermaphroditism	2005-02-01	no assertion criteria provided	clinical testing