NM_000348.4(SRD5A2):c.571G>A (p.Gly191Arg) AND 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 12, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003827606.2

Allele description [Variation Report for NM_000348.4(SRD5A2):c.571G>A (p.Gly191Arg)]

NM_000348.4(SRD5A2):c.571G>A (p.Gly191Arg)

Gene:

SRD5A2:steroid 5 alpha-reductase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.1

Genomic location:

Preferred name:

NM_000348.4(SRD5A2):c.571G>A (p.Gly191Arg)

HGVS:

NC_000002.12:g.31529434C>T
NG_008365.1:g.56538G>A
NG_008365.2:g.138575G>A
NM_000348.4:c.571G>AMANE SELECT
NP_000339.2:p.Gly191Arg
NC_000002.11:g.31754504C>T

Protein change:

G191R

Molecular consequence:

NM_000348.4:c.571G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (PPSH)
Synonyms:: Pseudovaginal perineoscrotal hypospadias; Male pseudohermaphroditism due to 5-alpha-reductase deficiency; Familial incomplete male pseudohermaphroditism, type 2; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009923; MedGen: C0268297; Orphanet: 753; OMIM: 264600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004629473	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 12, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31186340, 31885560, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004629473

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 12, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

New insights into 5α-reductase type 2 deficiency based on a multi-centre study: regional distribution and genotype-phenotype profiling of SRD5A2 in 190 Chinese patients.

Gui B, Song Y, Su Z, Luo FH, Chen L, Wang X, Chen R, Yang Y, Wang J, Zhao X, Fan L, Liu X, Wang Y, Chen S, Gong C.

J Med Genet. 2019 Oct;56(10):685-692. doi: 10.1136/jmedgenet-2018-105915. Epub 2019 Jun 11.

PubMed [citation]

PMID:: 31186340

Characterising SRD5A2 Gene Variants in 37 Indonesian Patients with 5-Alpha-Reductase Type 2 Deficiency.

Marzuki NS, Idris FP, Kartapradja HD, Harahap AR, Batubara JRL.

Int J Endocrinol. 2019;2019:7676341. doi: 10.1155/2019/7676341.

PubMed [citation]

PMID:: 31885560
PMCID:: PMC6914983

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004629473.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 191 of the SRD5A2 protein (p.Gly191Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with steroid-5 alpha-reductase deficiency (PMID: 31186340, 31885560). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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