ClinVar Miner

Submissions for variant NM_000348.4(SRD5A2):c.377A>G (p.Gln126Arg) (rs368386747)

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Total submissions: 4
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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 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 126 of the SRD5A2 protein (p.Gln126Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs368386747, ExAC 0.04%). This variant has been reported in many individuals affected with disorders of sex development (PMID: 1522235, 8262007, 15770495, 21631525, 27070133). Each case were compound heterozygous with a second SRD5A2 variant, or homozygous. This variant has also been observed to segregate with the disorder in multiple families (PMID: 15770495, 21631525, 22272144). ClinVar contains an entry for this variant (Variation ID: 372519). Experimental studies have shown that this missense change results in significant decrease in both protein half-life and enzyme activity, compared to wild-type (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].
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

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