Published functional studie demonstrates reduced testosterone binding (Wigley et al., 1994); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28544750, 28110336, 1522235, 7608269, 10458450, 9745434, 8784107, 8110760, 21402750)
ClinVar Genomic variation as it relates to human health
NM_000348.4(SRD5A2):c.692A>G (p.His231Arg)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000348.4(SRD5A2):c.692A>G (p.His231Arg)
Variation ID: 3346 Accession: VCV000003346.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p23.1 2: 31529313 (GRCh38) [ NCBI UCSC ] 2: 31754383 (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 Jun 23, 2016 Feb 14, 2024 Jan 31, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000348.4:c.692A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000339.2:p.His231Arg missense NC_000002.12:g.31529313T>C NC_000002.11:g.31754383T>C NG_008365.1:g.56659A>G - Protein change
- H231R
- Other names
- -
- Canonical SPDI
- NC_000002.12:31529312:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00015
Exome Aggregation Consortium (ExAC) 0.00016
The Genome Aggregation Database (gnomAD) 0.00016
- 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 |
321 | 350 | |
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 (3) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV000003510.12 | |
| Pathogenic (4) |
criteria provided, single submitter
|
Jul 15, 2020 | RCV001552751.6 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jul 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001773498.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Published functional studie demonstrates reduced testosterone binding (Wigley et al., 1994); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this … (more)
Published functional studie demonstrates reduced testosterone binding (Wigley et al., 1994); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28544750, 28110336, 1522235, 7608269, 10458450, 9745434, 8784107, 8110760, 21402750) (less)
|
|
|
Pathogenic
(Jan 31, 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: SCV000830869.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 231 of the SRD5A2 protein (p.His231Arg). … (more)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 231 of the SRD5A2 protein (p.His231Arg). This variant is present in population databases (rs121434251, gnomAD 0.03%). This missense change has been observed in individual(s) with 5 alpha-reductase 2 deficiency (PMID: 1522235, 7608269, 8706317, 8723114, 9745434, 27899157, 28544750). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3346). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SRD5A2 protein function. Experimental studies have shown that this missense change affects SRD5A2 function (8110760.1522235). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 01, 1998)
|
no assertion criteria provided
Method: literature only
|
PSEUDOVAGINAL PERINEOSCROTAL HYPOSPADIAS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023668.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2016 |
Comment on evidence:
For discussion of the his231-to-arg (H231R) mutation in the SRD5A2 gene that was found in compound heterozygous state in 3 brothers with pseudovaginal perineoscrotal hypospadias … (more)
For discussion of the his231-to-arg (H231R) mutation in the SRD5A2 gene that was found in compound heterozygous state in 3 brothers with pseudovaginal perineoscrotal hypospadias (PPSH; 264600) by Nordenskjold and Ivarsson (1998), see 607306.0010. (less)
|
|
|
Pathogenic
(Jun 12, 2017)
|
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: SCV000692400.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807053.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965000.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Pathogenic
(Sep 01, 2022)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV003840082.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
DNA sequence analysis of the SRD5A2 gene demonstrated two sequence changes. The first sequence change, c.692A>G, is located in exon 4 and results in an … (more)
DNA sequence analysis of the SRD5A2 gene demonstrated two sequence changes. The first sequence change, c.692A>G, is located in exon 4 and results in an amino acid change, p.His231Arg. The p.His231Arg change affects a highly conserved amino acid residue located in a domain of the SRD5A2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.His231Arg substitution. This pathogenic sequence change has previously been described in individuals with SRD5A2-related disorders in the homozygous or compound heterozygous state (PMID: 27899157, 8706317, 9745434, 1522235). This sequence change has been described in the gnomAD database with a frequency of 0.03% in the European subpopulation (dbSNP rs121434251). These collective evidences indicate that this sequence change is pathogenic. (less)
|
Comment:
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 231 of the SRD5A2 protein (p.His231Arg). This variant is present in population databases (rs121434251, gnomAD 0.03%). This missense change has been observed in individual(s) with 5 alpha-reductase 2 deficiency (PMID: 1522235, 7608269, 8706317, 8723114, 9745434, 27899157, 28544750). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3346). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SRD5A2 protein function. Experimental studies have shown that this missense change affects SRD5A2 function (8110760.1522235). For these reasons, this variant has been classified as Pathogenic.
Comment:
DNA sequence analysis of the SRD5A2 gene demonstrated two sequence changes. The first sequence change, c.692A>G, is located in exon 4 and results in an amino acid change, p.His231Arg. The p.His231Arg change affects a highly conserved amino acid residue located in a domain of the SRD5A2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.His231Arg substitution. This pathogenic sequence change has previously been described in individuals with SRD5A2-related disorders in the homozygous or compound heterozygous state (PMID: 27899157, 8706317, 9745434, 1522235). This sequence change has been described in the gnomAD database with a frequency of 0.03% in the European subpopulation (dbSNP rs121434251). These collective evidences indicate that this sequence change is pathogenic.
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:
Published functional studie demonstrates reduced testosterone binding (Wigley et al., 1994); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28544750, 28110336, 1522235, 7608269, 10458450, 9745434, 8784107, 8110760, 21402750)
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 231 of the SRD5A2 protein (p.His231Arg). This variant is present in population databases (rs121434251, gnomAD 0.03%). This missense change has been observed in individual(s) with 5 alpha-reductase 2 deficiency (PMID: 1522235, 7608269, 8706317, 8723114, 9745434, 27899157, 28544750). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3346). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SRD5A2 protein function. Experimental studies have shown that this missense change affects SRD5A2 function (8110760.1522235). For these reasons, this variant has been classified as Pathogenic.
Comment:
DNA sequence analysis of the SRD5A2 gene demonstrated two sequence changes. The first sequence change, c.692A>G, is located in exon 4 and results in an amino acid change, p.His231Arg. The p.His231Arg change affects a highly conserved amino acid residue located in a domain of the SRD5A2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.His231Arg substitution. This pathogenic sequence change has previously been described in individuals with SRD5A2-related disorders in the homozygous or compound heterozygous state (PMID: 27899157, 8706317, 9745434, 1522235). This sequence change has been described in the gnomAD database with a frequency of 0.03% in the European subpopulation (dbSNP rs121434251). These collective evidences indicate that this sequence change is pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Unexpected ethical dilemmas in sex assignment in 46,XY DSD due to 5-alpha reductase type 2 deficiency. | Byers HM | American journal of medical genetics. Part C, Seminars in medical genetics | 2017 | PMID: 28544750 |
| Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. | Eggers S | Genome biology | 2016 | PMID: 27899157 |
| Molecular characterization of 5 alpha-reductase type 2 deficiency and fertility in a Swedish family. | Nordenskjöld A | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9745434 |
| Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency. | Sinnecker GH | American journal of medical genetics | 1996 | PMID: 8723114 |
| Steroid 5 alpha-reductase 2 deficiency: virilization in early infancy may be due to partial function of mutant enzyme. | Forti G | Clinical endocrinology | 1996 | PMID: 8706317 |
| Molecular study of the 5 alpha-reductase type 2 gene in three European families with 5 alpha-reductase deficiency. | Boudon C | The Journal of clinical endocrinology and metabolism | 1995 | PMID: 7608269 |
| Molecular genetics of steroid 5 alpha-reductase 2 deficiency. | Thigpen AE | The Journal of clinical investigation | 1992 | PMID: 1522235 |
Text-mined citations for rs121434251 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.