Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000003501 | SCV000948445 | pathogenic | 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency | 2023-11-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 246 of the SRD5A2 protein (p.Arg246Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with steroid-5 alpha-reductase deficiency/46,XY disorder of sex development (PMID: 835597, 1406794, 1522235, 15528927, 27070133). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3337). 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: 1406794, 8110760). This variant disrupts the p.Arg246 amino acid residue in SRD5A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1522235, 19492581, 20190539, 20493473, 26446026). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001574452 | SCV001801272 | pathogenic | not provided | 2020-07-15 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate decreased enzymatic activity (Thigpen et al., 1992); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15528927, 21631525, 1406794, 15770495, 8626825, 20850730, 1522235) |
| OMIM | RCV000003501 | SCV000023659 | pathogenic | 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency | 1996-05-01 | no assertion criteria provided | literature only |