NM_000348.4(SRD5A2):c.548-2A>C AND 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 27, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000686310.6

Allele description [Variation Report for NM_000348.4(SRD5A2):c.548-2A>C]

NM_000348.4(SRD5A2):c.548-2A>C

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.548-2A>C

HGVS:

NC_000002.12:g.31529459T>G
NG_008365.1:g.56513A>C
NG_008365.2:g.138550A>C
NM_000348.4:c.548-2A>CMANE SELECT
NC_000002.11:g.31754529T>G
NM_000348.3:c.548-2A>C

Links:

dbSNP: rs61750397

NCBI 1000 Genomes Browser:

rs61750397

Molecular consequence:

NM_000348.4:c.548-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000813823	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 27, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21147889, 28938747, 16199547, 1406794, 1944596, 28492532
SCV002792592	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000813823

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 27, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002792592

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 2, 2021)

unknown

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

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

Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development.

Nixon R, Cerqueira V, Kyriakou A, Lucas-Herald A, McNeilly J, McMillan M, Purvis AI, Tobias ES, McGowan R, Ahmed SF.

Hum Reprod. 2017 Oct 1;32(10):2130-2137. doi: 10.1093/humrep/dex280.

PubMed [citation]

PMID:: 28938747
PMCID:: PMC5850224

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000813823.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 97408). Disruption of this splice site has been observed in individual(s) with disorders of sex development (PMID: 21147889, 28938747). This variant is present in population databases (rs61750397, gnomAD 0.005%). This sequence change affects an acceptor splice site in intron 3 of the SRD5A2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SRD5A2 are known to be pathogenic (PMID: 1406794, 1944596).

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002792592.1

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

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

Last Updated: Feb 20, 2024

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