NM_000348.4(SRD5A2):c.586G>A (p.Gly196Ser) AND 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Feb 27, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000003509.11

Allele description [Variation Report for NM_000348.4(SRD5A2):c.586G>A (p.Gly196Ser)]

NM_000348.4(SRD5A2):c.586G>A (p.Gly196Ser)

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.586G>A (p.Gly196Ser)
HGVS:
  • NC_000002.12:g.31529419C>T
  • NG_008365.1:g.56553G>A
  • NM_000348.4:c.586G>AMANE SELECT
  • NP_000339.2:p.Gly196Ser
  • NC_000002.11:g.31754489C>T
  • NM_000348.3:c.586G>A
Protein change:
G196S; GLY196SER
Links:
OMIM: 607306.0010; dbSNP: rs121434250
NCBI 1000 Genomes Browser:
rs121434250
Molecular consequence:
  • NM_000348.4:c.586G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
Identifiers:
MONDO: MONDO:0009923; MedGen: C0268297; Orphanet: 753; OMIM: 264600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000023667OMIMno assertion criteria providedPathogenic
(Sep 1, 1998)
germlineliterature only

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

SCV000631425Invitaecriteria provided, single submitter
Pathogenic
(Feb 27, 2019)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000692393Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospitalno assertion criteria providedPathogenic
(Apr 19, 2011)
germlineclinical testing

SCV000923606Genomic Research Center,Shahid Beheshti University of Medical Sciencescriteria provided, single submitter
Uncertain significance
(Jan 1, 2019)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Steroid 5 alpha-reductase 2 deficiency: virilization in early infancy may be due to partial function of mutant enzyme.

Forti G, Falchetti A, Santoro S, Davis DL, Wilson JD, Russell DW.

Clin Endocrinol (Oxf). 1996 Apr;44(4):477-82.

PubMed [citation]
PMID:
8706317

Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients.

Maimoun L, Philibert P, Cammas B, Audran F, Bouchard P, Fenichel P, Cartigny M, Pienkowski C, Polak M, Skordis N, Mazen I, Ocal G, Berberoglu M, Reynaud R, Baumann C, Cabrol S, Simon D, Kayemba-Kay's K, De Kerdanet M, Kurtz F, Leheup B, Heinrichs C, et al.

J Clin Endocrinol Metab. 2011 Feb;96(2):296-307. doi: 10.1210/jc.2010-1024. Epub 2010 Dec 8.

PubMed [citation]
PMID:
21147889
See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000023667.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

Nordenskjold and Ivarsson (1998) investigated the molecular background of type II 5-alpha-reductase deficiency (PPSH; 264600) in a Swedish family with no known consanguinity and in which males affected with pseudovaginal perineoscrotal hypospadias were fertile. The 3 male sibs were born with ambiguous external genitalia, and the diagnosis of 5-alpha-reductase deficiency was established at the ages of 16, 14, and 10, respectively. All 3 sibs underwent surgery for hypospadias repair. At least 2 of the brothers are demonstrably fertile. Molecular analysis showed that the 3 brothers were compound heterozygotes, carrying 2 different mutations in exon 4 of the SRD5A2 gene. The 2 mutations, gly196 to ser (G196S) and his231 to arg (H231R; 607306.0011), had previously been described and were reported to give rise to partially functioning enzymes, which may explain the milder phenotype, including the observed fertility (Thigpen et al., 1992; Forti et al., 1996).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000631425.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces glycine with serine at codon 196 of the SRD5A2 protein (p.Gly196Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs121434250, ExAC 0.04%). This variant has been reported as homozygous, or as heterozygous with a second rare variant in multiple families affected with 5a-reductase type 2 deficiency (PMID: 21147889, 21402750, 18391525, 9745434, 24737579). ClinVar contains an entry for this variant (Variation ID: 3345). Experimental studies have shown that this variant causes a reduced affinity for NADPH and an overall reduction in 5a-reductase enzyme activity (PMID: 1522235). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital, SCV000692393.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Genomic Research Center,Shahid Beheshti University of Medical Sciences, SCV000923606.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Sep 7, 2021

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