ClinVar Genomic variation as it relates to human health
NM_000348.4(SRD5A2):c.586G>A (p.Gly196Ser)
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.
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(3); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000348.4(SRD5A2):c.586G>A (p.Gly196Ser)
Variation ID: 3345 Accession: VCV000003345.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.1 2: 31529419 (GRCh38) [ NCBI UCSC ] 2: 31754489 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 28, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000348.4:c.586G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000339.2:p.Gly196Ser missense NC_000002.12:g.31529419C>T NC_000002.11:g.31754489C>T NG_008365.1:g.56553G>A - Protein change
- G196S
- Other names
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- Canonical SPDI
- NC_000002.12:31529418: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00014
The Genome Aggregation Database (gnomAD) 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00015
1000 Genomes Project 30x 0.00016
Exome Aggregation Consortium (ExAC) 0.00022
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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SRD5A2 | - | - |
GRCh38 GRCh37 |
313 | 341 |
Conditions - Germline
Condition
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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
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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. |
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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000003509.21 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2020 | RCV001269804.2 |
Submissions - Germline
Classification
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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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Likely pathogenic
(Jan 31, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450075.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(May 06, 2021)
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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:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768021.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
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 pseudovaginal perineoscrotal hypospadias (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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (37 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0600 - Variant is located in the annotated steroid dehydrogenase domain (NCBI, PDB). (I) 0702 – Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Residue 196 is considered to be a hotspot, with alternative changes to aspartic acid and arginine previously reported in individuals with pseudovaginal perineoscrotal hypospadias (MIM#264600) (ClinVar, PMIDs: 21402750, 28663096, 32346305). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported, in either a homozygous or compound heterozygous state, in multiple individuals with pseudovaginal perineoscrotal hypospadias (MIM#264600) (ClinVar, HGMD, PMIDs: 1522235, 25248670, 28110336). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant has been shown the result in decreased enzyme activity and a reduced affinity for NADPH (PMID: 1522235). (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
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000631425.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 196 of the SRD5A2 protein (p.Gly196Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 196 of the SRD5A2 protein (p.Gly196Ser). This variant is present in population databases (rs121434250, gnomAD 0.03%). This missense change has been observed in individual(s) with steroid 5-alpha-reductase deficiency (PMID: 18391525, 21147889, 21402750). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3345). 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: 1522235). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: yes
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000923606.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Number of individuals with the variant: 1
Sex: male
Geographic origin: Iran
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Pathogenic
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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Clinical Biochemistry Laboratory, Health Services Laboratory
Accession: SCV004190304.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Comment:
ACMG:PS5 PM2 PM3 PP4 PP5
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Pathogenic
(Sep 01, 1998)
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no assertion criteria provided
Method: literature only
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PSEUDOVAGINAL PERINEOSCROTAL HYPOSPADIAS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023667.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2016 |
Comment on evidence:
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 … (more)
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). (less)
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Pathogenic
(Apr 19, 2011)
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no assertion criteria provided
Method: clinical testing
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3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692393.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide. | Batista RL | The application of clinical genetics | 2020 | PMID: 32346305 |
Genotype-phenotype correlation and identification of two novel SRD5A2 mutations in 33 Chinese patients with hypospadias. | Yuan S | Steroids | 2017 | PMID: 28663096 |
New Territory for an Old Disease: 5-Alpha-Reductase Type 2 Deficiency in Bulgaria. | Andonova S | Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation | 2017 | PMID: 28110336 |
Disorders of sex development: a genetic study of patients in a multidisciplinary clinic. | Laino L | Endocrine connections | 2014 | PMID: 25248670 |
Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic. | Berra M | European journal of endocrinology | 2011 | PMID: 21402750 |
Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients. | Maimoun L | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 21147889 |
Early diagnosis of 5alpha-reductase deficiency in newborns. | Bertelloni S | Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation | 2007 | PMID: 18391525 |
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 |
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 genetics of steroid 5 alpha-reductase 2 deficiency. | Thigpen AE | The Journal of clinical investigation | 1992 | PMID: 1522235 |
Text-mined citations for rs121434250 ...
HelpRecord last updated Mar 05, 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.