Submissions for variant NM_000348.4(SRD5A2):c.704A>T (p.Tyr235Phe)

gnomAD frequency: 0.00001  dbSNP: rs772283403

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000529458	SCV000631435	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2023-02-10	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 235 of the SRD5A2 protein (p.Tyr235Phe). 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 2 deficiency (PMID: 8110760, 12699446, 16181229, 17609295, 21147889, 25266188, 27070133). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 459644). 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. For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV000529458	SCV001167590	pathogenic	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency	2018-09-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002287421	SCV002578003	pathogenic	Hypergonadotropic hypogonadism	2022-07-27	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PS4,PP5,BP1