Submissions for variant NM_000197.2(HSD17B3):c.239G>A (p.Arg80Gln)

gnomAD frequency: 0.00009  dbSNP: rs119481075

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255553	SCV000322436	pathogenic	not provided	2022-03-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant reduction in enzyme activity (Geissler et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25383892, 8075637, 23295294, 22857144, 22445608, 10599740, 27163392, 29566152, 33984517, 8626842, 31589614, 33144682, 33516834, 33586216)
Revvity Omics, Revvity	RCV000005150	SCV002025033	pathogenic	Testosterone 17-beta-dehydrogenase deficiency	2019-08-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255553	SCV002242089	pathogenic	not provided	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 80 of the HSD17B3 protein (p.Arg80Gln). This variant is present in population databases (rs119481075, gnomAD 0.01%). This missense change has been observed in individuals with 17-beta hydroxysteroid dehydrogenase 3 deficiency (PMID: 8626842, 17551466, 22445608, 23295294, 24025597). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4874). 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 expected to disrupt HSD17B3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HSD17B3 function (PMID: 8075637, 12429500). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000005150	SCV002809687	pathogenic	Testosterone 17-beta-dehydrogenase deficiency	2021-07-25	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000005150	SCV005086696	pathogenic	Testosterone 17-beta-dehydrogenase deficiency	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pseudohermaphroditism, male, with gynecomastia (MIM#264300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated short chain dehydrogenase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with differences of sex development, both as homozygotes or compound heterozygotes; and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMIDs: 22445608, 27898418, 36606580). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000005150	SCV000025327	pathogenic	Testosterone 17-beta-dehydrogenase deficiency	1996-05-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000581347	SCV000692115	pathogenic	Pseudohermaphroditism	2007-07-13	no assertion criteria provided	clinical testing