The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000459645). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:26446026). A different missense change at the same codon (p.Arg245Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003337). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_000348.4(SRD5A2):c.737G>A (p.Arg246Gln)
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.
(6)
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
6
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.737G>A (p.Arg246Gln)
Variation ID: 459645 Accession: VCV000459645.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p23.1 2: 31526224 (GRCh38) [ NCBI UCSC ] 2: 31751294 (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 Dec 26, 2017 Oct 8, 2024 Jan 22, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000348.4:c.737G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000339.2:p.Arg246Gln missense NC_000002.12:g.31526224C>T NC_000002.11:g.31751294C>T NG_008365.1:g.59748G>A - Protein change
- R246Q
- Other names
- -
- Canonical SPDI
- NC_000002.12:31526223:C:T
-
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.
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0.00040 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00023
1000 Genomes Project 0.00040
Exome Aggregation Consortium (ExAC) 0.00058
1000 Genomes Project 30x 0.00062
- 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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2024 | RCV000546486.22 | |
|
SRD5A2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 20, 2024 | RCV004755953.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
|
Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology
Accession: SCV001960992.2
First in ClinVar: Oct 08, 2021 Last updated: Dec 04, 2021 |
Clinical Features:
Primary amenorrhea (present) , Clitoral hypertrophy (present) , Ambiguous genitalia (present) , Absence of secondary sex characteristics (present) , Uterus absent (present) , Female external … (more)
Primary amenorrhea (present) , Clitoral hypertrophy (present) , Ambiguous genitalia (present) , Absence of secondary sex characteristics (present) , Uterus absent (present) , Female external genitalia in individual with 46,XY karyotype (present) (less)
Age: 10-19 years
Sex: female
Testing laboratory: Medgenome
Date variant was reported to submitter: 2020-09-25
|
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521715.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000459645). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:26446026). A different missense change at the same codon (p.Arg245Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003337). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Ambiguous genitalia (present) , Autism (present)
|
|
|
Likely pathogenic
(Nov 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238741.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 22, 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: SCV000631436.6
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 246 of the SRD5A2 protein (p.Arg246Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 246 of the SRD5A2 protein (p.Arg246Gln). This variant is present in population databases (rs9332967, gnomAD 0.1%). This missense change has been observed in individual(s) with 5-alpha reductase type 2 deficiency (PMID: 1522235, 2665940, 10718838, 14594182, 18097518, 18717241, 19492581, 20190539, 20493473, 20583543, 23329752, 25899528, 26446026, 26980298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 459645). 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. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jul 21, 2009)
|
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: SCV000692401.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
Pathogenic
(May 20, 2024)
|
no assertion criteria provided
Method: clinical testing
|
SRD5A2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005345539.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The SRD5A2 c.737G>A variant is predicted to result in the amino acid substitution p.Arg246Gln. This variant has been reported in the homozygous and compound heterozygous … (more)
The SRD5A2 c.737G>A variant is predicted to result in the amino acid substitution p.Arg246Gln. 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 1, Thigpen et al. 1992. PubMed ID: 1522235; Table 3, Ko et al. 2010. PubMed ID: 20190539; Table 3, Jia et al. 2018. PubMed ID: 29643321). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD. An alternate nucleotide substitution affecting the same amino acid (p.Arg246Trp) has been reported in multiple individuals with steroid 5-alpha-reductase deficiency (Table 1, Abacı et al. 2018. PubMed ID: 30132287). The c.737G>A (p.Arg246Gln) variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 246 of the SRD5A2 protein (p.Arg246Gln). This variant is present in population databases (rs9332967, gnomAD 0.1%). This missense change has been observed in individual(s) with 5-alpha reductase type 2 deficiency (PMID: 1522235, 2665940, 10718838, 14594182, 18097518, 18717241, 19492581, 20190539, 20493473, 20583543, 23329752, 25899528, 26446026, 26980298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 459645). 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. For these reasons, this variant has been classified as Pathogenic.
Comment:
The SRD5A2 c.737G>A variant is predicted to result in the amino acid substitution p.Arg246Gln. 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 1, Thigpen et al. 1992. PubMed ID: 1522235; Table 3, Ko et al. 2010. PubMed ID: 20190539; Table 3, Jia et al. 2018. PubMed ID: 29643321). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD. An alternate nucleotide substitution affecting the same amino acid (p.Arg246Trp) has been reported in multiple individuals with steroid 5-alpha-reductase deficiency (Table 1, Abacı et al. 2018. PubMed ID: 30132287). The c.737G>A (p.Arg246Gln) variant is interpreted as 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:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000459645). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:26446026). A different missense change at the same codon (p.Arg245Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003337). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 246 of the SRD5A2 protein (p.Arg246Gln). This variant is present in population databases (rs9332967, gnomAD 0.1%). This missense change has been observed in individual(s) with 5-alpha reductase type 2 deficiency (PMID: 1522235, 2665940, 10718838, 14594182, 18097518, 18717241, 19492581, 20190539, 20493473, 20583543, 23329752, 25899528, 26446026, 26980298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 459645). 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. For these reasons, this variant has been classified as Pathogenic.
Comment:
The SRD5A2 c.737G>A variant is predicted to result in the amino acid substitution p.Arg246Gln. 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 1, Thigpen et al. 1992. PubMed ID: 1522235; Table 3, Ko et al. 2010. PubMed ID: 20190539; Table 3, Jia et al. 2018. PubMed ID: 29643321). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD. An alternate nucleotide substitution affecting the same amino acid (p.Arg246Trp) has been reported in multiple individuals with steroid 5-alpha-reductase deficiency (Table 1, Abacı et al. 2018. PubMed ID: 30132287). The c.737G>A (p.Arg246Gln) variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic Alterations of Anaplastic Thyroid Carcinoma Detected by Targeted Massive Parallel Sequencing in a BRAF(V600E) Mutation-Prevalent Area. | Jeon MJ | Thyroid : official journal of the American Thyroid Association | 2016 | PMID: 26980298 |
| Homozygous p.R246Q Mutation and Impaired Spermatogenesis: Long Term Follow-up of 4 Children from One Family with 5 Alpha Reductase 2 Deficiency. | Shabir I | Indian journal of pediatrics | 2016 | PMID: 26446026 |
| Phenotype and molecular characteristics in 45 Chinese children with 5α-reductase type 2 deficiency from South China. | Cheng J | Clinical endocrinology | 2015 | PMID: 25899528 |
| Clinical and genetic analysis of three Chinese patients with steroid 5α-reductase type 2 deficiency. | Yang Y | Journal of pediatric endocrinology & metabolism : JPEM | 2012 | PMID: 23329752 |
| Molecular diagnosis of 46,XY DSD and identification of a novel 8 nucleotide deletion in exon 1 of the SRD5A2 gene. | Nagaraja MR | Journal of pediatric endocrinology & metabolism : JPEM | 2010 | PMID: 20583543 |
| Semen analysis and successful paternity by intracytoplasmic sperm injection in a man with steroid 5α-reductase-2 deficiency. | Matsubara K | Fertility and sterility | 2010 | PMID: 20493473 |
| Clinical characterization and analysis of the SRD5A2 gene in six Korean patients with 5alpha-reductase type 2 deficiency. | Ko JM | Hormone research in paediatrics | 2010 | PMID: 20190539 |
| Genetic analysis of the SRD5A2 gene in Indian patients with 5alpha-reductase deficiency. | Sahu R | Journal of pediatric endocrinology & metabolism : JPEM | 2009 | PMID: 19492581 |
| Molecular analysis of the AR and SRD5A2 genes in patients with 46,XY disorders of sex development. | Choi JH | Journal of pediatric endocrinology & metabolism : JPEM | 2008 | PMID: 18717241 |
| Molecular diagnosis of 5alpha-reductase-2 gene mutation in two Indian families with male pseudohermaphroditism. | Eunice M | Asian journal of andrology | 2008 | PMID: 18097518 |
| 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 |
| Identification of missense mutations in the SRD5A2 gene from patients with steroid 5alpha-reductase 2 deficiency. | Vilchis F | Clinical endocrinology | 2000 | PMID: 10718838 |
| Molecular genetics of steroid 5 alpha-reductase 2 deficiency. | Thigpen AE | The Journal of clinical investigation | 1992 | PMID: 1522235 |
| Modularity in promoters and enhancers. | Dynan WS | Cell | 1989 | PMID: 2665940 |
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Text-mined citations for rs9332967 ...
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 Nov 25, 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.