ClinVar Miner

Submissions for variant NM_000348.4(SRD5A2):c.598G>A (p.Glu200Lys)

gnomAD frequency: 0.00002  dbSNP: rs756853742
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000582995 SCV001395940 pathogenic 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 200 of the SRD5A2 protein (p.Glu200Lys). This variant is present in population databases (rs756853742, gnomAD 0.02%). This missense change has been observed in individual(s) with ambiguous genitalia and/or steroid 5-alpha-reductase deficiency (PMID: 9208814; Invitae). ClinVar contains an entry for this variant (Variation ID: 492905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SRD5A2 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000582995 SCV002564428 uncertain significance 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 2022-05-21 criteria provided, single submitter clinical testing A homozygous missense variation in exon 4 of the SRD5A2 gene that results in the amino acid substitution of Lysine for glutamic at codon 200 was detected. The observed variant c.598G>A (p.Glu200Lys) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by SIFT. The reference codon is conserved across species.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000582995 SCV004038788 pathogenic 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 2023-08-03 criteria provided, single submitter clinical testing Variant summary: SRD5A2 c.595G>A (p.Glu199Lys) results in a conservative amino acid change located in the C-terminal domain (IPR001104) of the encoded protein sequence. This variant is also known as c.598G>A (p.Glu200Lys) in RefSeq NM_000348 and in the literature. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248858 control chromosomes (i.e., 6 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.595G>A has been reported in the literature in multiple individuals affected with 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (e.g., Anwar_1997, Arboleda_2013, Annamalai_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9208814, 22435390, 22362597). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000582995 SCV000692394 pathogenic 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency 2012-12-26 no assertion criteria provided clinical testing

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