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NM_000348.4(SRD5A2):c.680G>A (p.Arg227Gln) AND 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency

Germline classification:
Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:
Jan 30, 2024
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:
RCV000288398.24

Allele description [Variation Report for NM_000348.4(SRD5A2):c.680G>A (p.Arg227Gln)]

NM_000348.4(SRD5A2):c.680G>A (p.Arg227Gln)

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.680G>A (p.Arg227Gln)
Other names:
NM_000348.3(SRD5A2):c.680G>A(p.Arg227Gln)
HGVS:
  • NC_000002.12:g.31529325C>T
  • NG_008365.1:g.56647G>A
  • NM_000348.4:c.680G>AMANE SELECT
  • NP_000339.2:p.Arg227Gln
  • NC_000002.11:g.31754395C>T
  • NM_000348.3:c.680G>A
Protein change:
R227Q; ARG227GLN
Links:
OMIM: 607306.0016; dbSNP: rs9332964
NCBI 1000 Genomes Browser:
rs9332964
Molecular consequence:
  • NM_000348.4:c.680G>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000597254Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(May 22, 2017)
germlineclinical testing

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

SCV000631431Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 30, 2024)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV000692398Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
no assertion criteria provided
Pathogenic
(Apr 12, 2016)
germlineclinical testing

SCV000803498SIB Swiss Institute of Bioinformatics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(May 31, 2018)
unknowncuration

PubMed (4)
[See all records that cite these PMIDs]

SCV001142316Reproductive Health Research and Development, BGI Genomics
no assertion criteria provided
Pathogenic
(Jan 6, 2020)
germlinecuration

SCV001422496Department of Medical Genetics, Hue University of Medicine and Pharmacy
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 15, 2019)
unknownclinical testing

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

SCV001482343Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
no assertion criteria provided
Pathogenic
(May 31, 2019)
inheritedresearch

SCV002557885Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Sep 2, 2022)
germlineclinical testing

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

SCV004174101Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
no assertion criteria provided
Pathogenicsomaticclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedinheritedyesnot providednot providednot providednot providednot providedresearch
not providedunknownyesnot providednot providednot providednot providednoclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedcuration
not providedsomaticyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Micropenis and the 5alpha-reductase-2 (SRD5A2) gene: mutation and V89L polymorphism analysis in 81 Japanese patients.

Sasaki G, Ogata T, Ishii T, Kosaki K, Sato S, Homma K, Takahashi T, Hasegawa T, Matsuo N.

J Clin Endocrinol Metab. 2003 Jul;88(7):3431-6.

PubMed [citation]
PMID:
12843198

Steroid 5alpha-reductase 2 deficiency in two generations of a non-consanguineous Chinese family.

Lee CY, Lam CW, Shek CC.

J Pediatr Endocrinol Metab. 2003 Oct-Nov;16(8):1197-201.

PubMed [citation]
PMID:
14594182
See all PubMed Citations (12)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000597254.1

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

From Invitae, SCV000631431.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the SRD5A2 protein (p.Arg227Gln). This variant is present in population databases (rs9332964, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with steroid 5-alpha-reductase deficiency (PMID: 12843198, 14594182, 19342739, 20736251, 22453073, 25605705, 25899528). It is commonly reported in individuals of East Asian ancestry (PMID: 12843198, 14594182, 19342739, 20736251, 22453073, 25605705, 25899528). ClinVar contains an entry for this variant (Variation ID: 3351). 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 not expected to disrupt SRD5A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SRD5A2 function (PMID: 10898110). 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, SCV000692398.1

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

From SIB Swiss Institute of Bioinformatics, SCV000803498.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (4)

Description

This variant is interpreted as a Likely Pathogenic, for Pseudovaginal perineoscrotal hypospadias, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PS3 => Well-established functional studies show a deleterious effect (PMID:10898110). PM2-Supporting => PM2 downgraded in strength to Supporting. PS4-Supporting => PS4 downgraded in strength to Supporting. Recurrently seen in non-related affected individuals (PMID:25899528). PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:15064320).

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

From Reproductive Health Research and Development, BGI Genomics, SCV001142316.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

NM_000348.3:c.680G>A in the SRD5A2 gene has an allele frequency of 0.006 in East Asian subpopulation in the gnomAD database. Cheng J et al. reported that the c.680G>A (p.Arg227Gln) mutation was identified in 16 homozygous patients, 17 compound heterozygous patients, eight heterozygous patients with 5-alpha-reductase type 2 deficiency (PMID: 25899528 ). Experimental studies have shown that this missense change reduces enzyme activity (PMID: 10898110). In addition, Cancio et al. reported a male pseudohermaphrodite patient harboring R227Q with a frameshift mutation from codon 219. These two variants were located in a different allele (PMID: 15064320). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP4.

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

From Department of Medical Genetics, Hue University of Medicine and Pharmacy, SCV001422496.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednoclinical testing PubMed (1)

Description

This variant, NM_000348.4:c.680G>A, was found in compound heterozygosity with the pathogenic variant NM_000348.4:c.485A>C.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providedPeripheral bloodnot providednot providednot providednot providednot provided

From Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital, SCV001482343.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot providednot providednot providednot providednot provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557885.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SRD5A2-related 5 alpha reductase deficiency (MIM#264600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (32 heterozygotes, 1 homozygote). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated 3-oxo-5-alpha-steroid 4-dehydrogenase domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple East Asian patients with 5α-reductase 2 deficiency (ClinVar, PMID: 32713132). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes reduced enzyme activity (PMID: 10898110). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

From Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital, SCV004174101.1

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

Last Updated: Jun 23, 2024