This variant, NM_000348.4:c.680G>A, was found in compound heterozygosity with the pathogenic variant NM_000348.4:c.485A>C.
ClinVar Genomic variation as it relates to human health
NM_000348.4(SRD5A2):c.680G>A (p.Arg227Gln)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(14)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of 2 Genotypes
- Identifiers
-
NM_000348.4(SRD5A2):c.680G>A (p.Arg227Gln)
Variation ID: 3351 Accession: VCV000003351.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.1 2: 31529325 (GRCh38) [ NCBI UCSC ] 2: 31754395 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2014 Oct 8, 2024 Jan 30, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000348.4:c.680G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000339.2:p.Arg227Gln missense NC_000002.12:g.31529325C>T NC_000002.11:g.31754395C>T NG_008365.1:g.56647G>A - Protein change
- R227Q
- Other names
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NM_000348.3(SRD5A2):c.680G>A(p.Arg227Gln)
- Canonical SPDI
- NC_000002.12:31529324:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00140 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00023
Exome Aggregation Consortium (ExAC) 0.00041
The Genome Aggregation Database (gnomAD), exomes 0.00047
1000 Genomes Project 0.00140
1000 Genomes Project 30x 0.00141
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| SRD5A2 | - | - |
GRCh38 GRCh37 |
319 | 348 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2003 | RCV000003515.4 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Apr 15, 2016 | RCV000083663.6 | |
| Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000288398.26 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 28, 2023 | RCV003313913.3 | |
|
SRD5A2-related disorder
|
Likely pathogenic (1) |
no assertion criteria provided
|
May 20, 2024 | RCV003944795.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Likely pathogenic
(May 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Pseudovaginal perineoscrotal hypospadias
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000597254.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(Nov 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
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3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Department of Medical Genetics, Hue University of Medicine and Pharmacy
Accession: SCV001422496.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
This variant, NM_000348.4:c.680G>A, was found in compound heterozygosity with the pathogenic variant NM_000348.4:c.485A>C.
Clinical Features:
Scrotum-like labia majora (present) , hypospadias (present) , micropenis (present) , clitoris-like phallus (present) , bilateral testis (present)
Family history: no
Age: 0-9 years
Geographic origin: Vietnam
Tissue: Peripheral blood
Testing laboratory: Gene Solutions, Medical Genetics Institute, Vietnam
Date variant was reported to submitter: 2019-06-12
Testing laboratory interpretation: Likely pathogenic
|
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Likely pathogenic
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803498.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Apr 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000340737.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
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Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000631431.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557885.3
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency (MONDO:0009923). (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 (less)
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Pathogenic
(Jul 01, 2003)
|
no assertion criteria provided
Method: literature only
|
MICROPENIS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023673.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2016 |
Comment on evidence:
In 3 Japanese patients with micropenis (see 264600), Sasaki et al. (2003) found a 680G-A transition in exon 4 of the SRD5A2 gene that resulted … (more)
In 3 Japanese patients with micropenis (see 264600), Sasaki et al. (2003) found a 680G-A transition in exon 4 of the SRD5A2 gene that resulted in an arg227-to-gln (R227Q) amino acid substitution. The mutation was found in compound heterozygosity in 2 patients and in homozygosity in 1. In in vitro biochemical studies, Makridakis et al. (2000) showed that R227Q reduces the maximum velocity of enzyme reaction, or V(max), to approximately 3.2% of normal activity. (less)
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Pathogenic
(May 31, 2019)
|
no assertion criteria provided
Method: research
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3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: yes
Allele origin:
inherited
|
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
Accession: SCV001482343.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
|
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Likely pathogenic
(May 20, 2024)
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no assertion criteria provided
Method: clinical testing
|
SRD5A2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004762852.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The SRD5A2 c.680G>A variant is predicted to result in the amino acid substitution p.Arg227Gln. This variant has been reported in the homozygous and compound heterozygous … (more)
The SRD5A2 c.680G>A variant is predicted to result in the amino acid substitution p.Arg227Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with steroid 5-alpha-reductase deficiency (see for example, Table 2, Hiort et al. 1996. PubMed ID: 8784107; Table 1, Kon et al. 2015. PubMed ID: 25605705; Table 2, Zhang et al. 2019. PubMed ID: 31219235). This variant is reported in 0.67% of alleles in individuals of East Asian descent in gnomAD. An in vitro experimental study has shown this variant markedly reduces enzyme activity (Table 2, Makridakis et al. 2000. PubMed ID: 10898110). This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Apr 12, 2016)
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no assertion criteria provided
Method: clinical testing
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692398.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
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Pathogenic
(Jan 06, 2020)
|
no assertion criteria provided
Method: curation
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142316.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Jul 28, 2023)
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no assertion criteria provided
Method: clinical testing
|
Autism spectrum disorder
Affected status: yes
Allele origin:
unknown
|
Gene Friend Way, National Innovation Center
Accession: SCV004013902.2
First in ClinVar: Jul 22, 2023 Last updated: Aug 30, 2023 |
Comment:
A nonsynonymous change known as R227Q in the SRD5A2 gene. The SRD5A2 gene encodes steroid 5-alpha-reductase, an enzyme which catalyzes the conversion of testosterone in … (more)
A nonsynonymous change known as R227Q in the SRD5A2 gene. The SRD5A2 gene encodes steroid 5-alpha-reductase, an enzyme which catalyzes the conversion of testosterone in the body. Some research shows that there is a role for the adrenal glands in ASD (PMID: 34493761). Variants of SRD5A2 related to autism/ autistic-like traits have been reported (PMID: 35042285, 23867117). (less)
Number of individuals with the variant: 8
Method: 800K direct targets snp array, validated with Sanger sequencing
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: yes
Allele origin:
somatic
|
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV004174101.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
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not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
University of Sydney Medical Foundation
Accession: SCV000115749.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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Comment:
Comment:
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).
Comment:
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.
Comment:
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 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency (MONDO:0009923). (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
Comment:
The SRD5A2 c.680G>A variant is predicted to result in the amino acid substitution p.Arg227Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with steroid 5-alpha-reductase deficiency (see for example, Table 2, Hiort et al. 1996. PubMed ID: 8784107; Table 1, Kon et al. 2015. PubMed ID: 25605705; Table 2, Zhang et al. 2019. PubMed ID: 31219235). This variant is reported in 0.67% of alleles in individuals of East Asian descent in gnomAD. An in vitro experimental study has shown this variant markedly reduces enzyme activity (Table 2, Makridakis et al. 2000. PubMed ID: 10898110). This variant is interpreted as likely pathogenic.
Comment:
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.
Comment:
A nonsynonymous change known as R227Q in the SRD5A2 gene. The SRD5A2 gene encodes steroid 5-alpha-reductase, an enzyme which catalyzes the conversion of testosterone in the body. Some research shows that there is a role for the adrenal glands in ASD (PMID: 34493761). Variants of SRD5A2 related to autism/ autistic-like traits have been reported (PMID: 35042285, 23867117).
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant, NM_000348.4:c.680G>A, was found in compound heterozygosity with the pathogenic variant NM_000348.4:c.485A>C.
Comment:
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).
Comment:
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.
Comment:
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 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency (MONDO:0009923). (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
Comment:
The SRD5A2 c.680G>A variant is predicted to result in the amino acid substitution p.Arg227Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with steroid 5-alpha-reductase deficiency (see for example, Table 2, Hiort et al. 1996. PubMed ID: 8784107; Table 1, Kon et al. 2015. PubMed ID: 25605705; Table 2, Zhang et al. 2019. PubMed ID: 31219235). This variant is reported in 0.67% of alleles in individuals of East Asian descent in gnomAD. An in vitro experimental study has shown this variant markedly reduces enzyme activity (Table 2, Makridakis et al. 2000. PubMed ID: 10898110). This variant is interpreted as likely pathogenic.
Comment:
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.
Comment:
A nonsynonymous change known as R227Q in the SRD5A2 gene. The SRD5A2 gene encodes steroid 5-alpha-reductase, an enzyme which catalyzes the conversion of testosterone in the body. Some research shows that there is a role for the adrenal glands in ASD (PMID: 34493761). Variants of SRD5A2 related to autism/ autistic-like traits have been reported (PMID: 35042285, 23867117).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical characteristics and genotype-phenotype correlations of 130 Chinese children in a high-homogeneity single-center cohort with 5α-reductase 2 deficiency. | Fan L | Molecular genetics & genomic medicine | 2020 | PMID: 32713132 |
| Phenotype and molecular characteristics in 45 Chinese children with 5α-reductase type 2 deficiency from South China. | Cheng J | Clinical endocrinology | 2015 | PMID: 25899528 |
| Molecular basis of non-syndromic hypospadias: systematic mutation screening and genome-wide copy-number analysis of 62 patients. | Kon M | Human reproduction (Oxford, England) | 2015 | PMID: 25605705 |
| A novel SRD5A2 mutation in a Taiwanese newborn with ambiguous genitalia. | Tsai MC | The Kaohsiung journal of medical sciences | 2012 | PMID: 22453073 |
| Five novel mutations of SRD5A2 found in eight Chinese patients with 46,XY disorders of sex development. | Nie M | Molecular human reproduction | 2011 | PMID: 20736251 |
| Diagnosis of 5alpha-reductase 2 deficiency: a local experience. | Chan AO | Hong Kong medical journal = Xianggang yi xue za zhi | 2009 | PMID: 19342739 |
| Compound heterozygous mutations in the SRD5A2 gene exon 4 in a male pseudohermaphrodite patient of Chinese origin. | Fernández-Cancio M | Journal of andrology | 2004 | PMID: 15064320 |
| Steroid 5alpha-reductase 2 deficiency in two generations of a non-consanguineous Chinese family. | Lee CY | Journal of pediatric endocrinology & metabolism : JPEM | 2003 | PMID: 14594182 |
| Micropenis and the 5alpha-reductase-2 (SRD5A2) gene: mutation and V89L polymorphism analysis in 81 Japanese patients. | Sasaki G | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12843198 |
| Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. | Makridakis NM | Pharmacogenetics | 2000 | PMID: 10898110 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SRD5A2 | - | - | - | - |
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Text-mined citations for rs9332964 ...
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Record last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.