Submissions for variant NM_000348.4(SRD5A2):c.680G>A (p.Arg227Gln)

gnomAD frequency: 0.00016  dbSNP: rs9332964

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000083663	SCV000340737	pathogenic	not provided	2016-04-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000288398	SCV000597254	likely pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2017-05-22	criteria provided, single submitter	clinical testing
Invitae	RCV000288398	SCV000631431	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the SRD5A2 protein (p.Arg227Gln). This variant is present in population databases (rs9332964, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with steroid 5-alpha-reductase deficiency (PMID: 12843198, 14594182, 19342739, 20736251, 22453073, 25605705, 25899528). It is commonly reported in individuals of East Asian ancestry (PMID: 12843198, 14594182, 19342739, 20736251, 22453073, 25605705, 25899528). ClinVar contains an entry for this variant (Variation ID: 3351). 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: 10898110). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000288398	SCV000803498	likely pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Pseudovaginal perineoscrotal hypospadias, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PS3 => Well-established functional studies show a deleterious effect (PMID:10898110). PM2-Supporting => PM2 downgraded in strength to Supporting. PS4-Supporting => PS4 downgraded in strength to Supporting. Recurrently seen in non-related affected individuals (PMID:25899528). PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:15064320).
Department of Medical Genetics, Hue University of Medicine and Pharmacy	RCV000288398	SCV001422496	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2019-11-15	criteria provided, single submitter	clinical testing	This variant, NM_000348.4:c.680G>A, was found in compound heterozygosity with the pathogenic variant NM_000348.4:c.485A>C.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000288398	SCV002557885	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2022-09-02	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 SRD5A2-related 5 alpha reductase deficiency (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 arginine to glutamine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (32 heterozygotes, 1 homozygote). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated 3-oxo-5-alpha-steroid 4-dehydrogenase domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple East Asian patients with 5α-reductase 2 deficiency (ClinVar, PMID: 32713132). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes reduced enzyme activity (PMID: 10898110). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003944795	SCV004762852	likely pathogenic	SRD5A2-related disorder	2023-11-16	criteria provided, single submitter	clinical testing	The SRD5A2 c.680G>A variant is predicted to result in the amino acid substitution p.Arg227Gln. This variant has been reported to be causative for steroid 5-alpha-reductase deficiency (OMIM #264600) in multiple affected individuals (Hiort et al. 1996. PubMed ID: 8784107; Kon et al. 2015. PubMed ID: 25605705; Nixon et al. 2017. PubMed ID: 28938747). This variant was reported to markedly reduce enzyme activity (Makridakis et al. 2000. PubMed ID: 10898110). This variant is reported in 0.67% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-31754395-C-T). This variant is interpreted as likely pathogenic.
OMIM	RCV000003515	SCV000023673	pathogenic	Micropenis	2003-07-01	no assertion criteria provided	literature only
University of Sydney Medical Foundation	RCV000083663	SCV000115749	not provided	not provided		no assertion provided	not provided
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000288398	SCV000692398	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2016-04-12	no assertion criteria provided	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000288398	SCV001142316	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2020-01-06	no assertion criteria provided	curation	NM_000348.3:c.680G>A in the SRD5A2 gene has an allele frequency of 0.006 in East Asian subpopulation in the gnomAD database. Cheng J et al. reported that the c.680G>A (p.Arg227Gln) mutation was identified in 16 homozygous patients, 17 compound heterozygous patients, eight heterozygous patients with 5-alpha-reductase type 2 deficiency (PMID: 25899528 ). Experimental studies have shown that this missense change reduces enzyme activity (PMID: 10898110). In addition, Cancio et al. reported a male pseudohermaphrodite patient harboring R227Q with a frameshift mutation from codon 219. These two variants were located in a different allele (PMID: 15064320). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP4.
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000288398	SCV001482343	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2019-05-31	no assertion criteria provided	research
Gene Friend Way, National Innovation Center	RCV003313913	SCV004013902	likely pathogenic	Autism spectrum disorder	2023-07-28	no assertion criteria provided	clinical testing	A nonsynonymous change known as R227Q in the SRD5A2 gene. The SRD5A2 gene encodes steroid 5-alpha-reductase, an enzyme which catalyzes the conversion of testosterone in the body. Some research shows that there is a role for the adrenal glands in ASD (PMID: 34493761). Variants of SRD5A2 related to autism/ autistic-like traits have been reported (PMID: 35042285, 23867117).
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000288398	SCV004174101	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency		no assertion criteria provided	clinical testing