Submissions for variant NM_000348.4(SRD5A2):c.607G>A (p.Gly203Ser)

gnomAD frequency: 0.00002  dbSNP: rs9332961

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535535	SCV000631427	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 203 of the SRD5A2 protein (p.Gly203Ser). This variant is present in population databases (rs9332961, gnomAD 0.09%). This missense change has been observed in individuals with 5alpha-reductase type 2 deficiency (PMID: 2154055, 9135696, 15266301, 19342739, 21147889, 23329752, 24665940, 25899528). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 459640). 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 not expected to disrupt SRD5A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SRD5A2 function (PMID: 21540559). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000535535	SCV002557118	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pseudovaginal perineoscrotal hypospadias (MIM#264600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (23 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Steroid_dh domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and reported in many homozygous and compound heterozygous individuals with severe hypospadias (ClinVar, PMID: 32713132, PMID: 15266301). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000535535	SCV005418805	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP4
Fulgent Genetics, Fulgent Genetics	RCV000535535	SCV005663645	likely pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2024-06-06	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000535535	SCV000692395	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2016-04-12	no assertion criteria provided	clinical testing