ClinVar Miner

Submissions for variant NM_000348.4(SRD5A2):c.578A>G (p.Asn193Ser) (rs763296857)

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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 RCV000534325 SCV000692392 pathogenic 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 2017-10-31 criteria provided, single submitter clinical testing
Invitae RCV000534325 SCV000631424 pathogenic 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 2017-01-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 193 of the SRD5A2 protein (p.Asn193Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs763296857, ExAC 0.006%). This variant has been reported in several individuals with ambiguous genitalia and 5 alpha-reductase deficiency, a number of whom were homozygous for this variant (PMID: 20850730, 20736251, 21631525, 24665940, 20019388, 23633205). An experimental study has shown that this missense change disrupts the ability of the SRD5A2 enzyme to bind the cofactor NADPH and convert testosterone to dihydrotestosterone in cell culture assays (PMID: 8110760). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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