ClinVar Miner

Submissions for variant NM_000348.4(SRD5A2):c.736C>T (p.Arg246Trp) (rs121434244)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000003501 SCV000948445 pathogenic 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 2018-10-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 246 of the SRD5A2 protein (p.Arg246Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with steroid-5 alpha-reductase deficiency/46,XY disorder of sex development in a large kindred and is present in several unrelated individuals with steroid-5 alpha-reductase deficiency (PMID: 835597, 1406794, 1522235, 27070133, 15528927). ClinVar contains an entry for this variant (Variation ID: 3337). Experimental studies have shown that this missense change decreases the half-life and enzymatic activity of the steroid-5 alpha-reductase protein (PMID: 1406794, 8110760). This variant disrupts the p.Arg246 amino acid residue in SRD5A2. Another variant that disrupts this residue has been observed in affected individuals (PMID: 26446026, 19492581, 20190539, 1522235, 20493473), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003501 SCV000023659 pathogenic 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 1996-05-01 no assertion criteria provided literature only

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