ClinVar Miner

Submissions for variant NM_000197.1(HSD17B3):c.239G>A (rs119481075)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255553 SCV000322436 pathogenic not provided 2017-07-13 criteria provided, single submitter clinical testing The R80Q pathogenic variant in the HSD17B3 gene has been reported previously in the homozygous and compound heterozygous state in multiple 46,XY individuals with pseudohermaphroditism and 17-beta hydroxysteroid dehydrogenase 3 deficiency, with virilization occurring at puberty (Rösler et al., 1996; Castro et al., 2012; Neocleous et al., 2012). This pathogenic variant likely represents an ancient founder mutation, responsible for its presence within the Gaza Arab population, Dutch, and Brazilian and Portuguese individuals of European descent (Rösler et al., 1996; Boehmer et al., 1999; Shammas et al., 2012). The R80Q variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R80Q variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across mammalian species. Expression analysis of R80Q in transfected cells demonstrated a marked reduction in enzyme activity (Geissler et al., 1994), with some residual activity detected upon prolonged incubation with substrate, which may explain the virilization that occurs at puberty (Rösler et al., 1996). Missense variants in the same (R80W) and nearby (N74T) residues have been reported in the Human Gene Mutation Database in association with HSD17B3-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R80Q as a pathogenic variant.
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

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