ClinVar Miner

Submissions for variant NM_000348.4(SRD5A2):c.271T>C (p.Tyr91His) (rs201175894)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582682 SCV000692382 pathogenic 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 2017-10-31 criteria provided, single submitter clinical testing
Invitae RCV000582682 SCV001220402 pathogenic 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 2019-02-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 91 of the SRD5A2 protein (p.Tyr91His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals and families affected with disorders of sex development (PMID: 21147889, 24737579, 288959874). ClinVar contains an entry for this variant (Variation ID: 492899). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Tyr91 amino acid residue in SRD5A2. Other variant(s) that disrupt this residue have been observed in individuals with SRD5A2-related conditions (PMID: 21631525, 8262007, 8110760), 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.

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