Submissions for variant NM_000348.4(SRD5A2):c.377A>G (p.Gln126Arg)

gnomAD frequency: 0.00009  dbSNP: rs368386747

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413020	SCV000490832	pathogenic	not provided	2016-03-18	criteria provided, single submitter	clinical testing	The Q126R missense change has been been reported in multiple individuals with 5-alpha reductase deficiency (Thigpen et al., 2002; Maimoun et al., 2011; Thigpen et al., 1992; Hackel et al., 2005). Additionally, functional studies indicate that Q126R abolishes the enzyme function of the steroid 5-alpha reductase enzyme to bind to testosterone (Wigley et al., 1994). Therefore, we interpret Q126R as a pathogenic variant.
Invitae	RCV000545602	SCV000631422	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 126 of the SRD5A2 protein (p.Gln126Arg). This variant is present in population databases (rs368386747, gnomAD 0.02%). This missense change has been observed in individuals with disorders of sex development (PMID: 1522235, 8262007, 15770495, 21631525, 22272144, 27070133). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372519). 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%. Experimental studies have shown that this missense change affects SRD5A2 function (PMID: 8110760). For these reasons, this variant has been classified as Pathogenic.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000545602	SCV001423617	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2018-07-06	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS3, PM2, PM3, PS4_Moderate, PP1, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], has been shown to cosegregate with disease in multiple affected family members [PP1], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Fulgent Genetics, Fulgent Genetics	RCV000545602	SCV002802050	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2022-02-16	criteria provided, single submitter	clinical testing
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000545602	SCV004190300	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2023-11-20	criteria provided, single submitter	clinical testing	ACMG:PS5 PM2 PM3 PP4 PP5
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000545602	SCV000692385	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2011-05-23	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000545602	SCV001760085	likely pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency		no assertion criteria provided	clinical testing