A homozygous missense variation in exon 4 of the SRD5A2 gene that results in the amino acid substitution of Lysine for glutamic at codon 200 was detected. The observed variant c.598G>A (p.Glu200Lys) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by SIFT. The reference codon is conserved across species.
ClinVar Genomic variation as it relates to human health
NM_000348.4(SRD5A2):c.598G>A (p.Glu200Lys)
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.
(4)
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.
Conflicting classifications of pathogenicity
Pathogenic(2); Uncertain significance(1)
Pathogenic(2); Uncertain significance(1)
4
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000348.4(SRD5A2):c.598G>A (p.Glu200Lys)
Variation ID: 492905 Accession: VCV000492905.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.1 2: 31529407 (GRCh38) [ NCBI UCSC ] 2: 31754477 (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 19, 2018 Feb 14, 2024 Dec 18, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000348.4:c.598G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000339.2:p.Glu200Lys missense NC_000002.12:g.31529407C>T NC_000002.11:g.31754477C>T NG_008365.1:g.56565G>A - Protein change
- E200K
- Other names
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p.Glu200Lys
- Canonical SPDI
- NC_000002.12:31529406: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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Unknown function
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
- 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 |
320 | 349 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Dec 18, 2023 | RCV000582995.11 |
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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Uncertain significance
(May 21, 2022)
|
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
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002564428.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
Comment:
A homozygous missense variation in exon 4 of the SRD5A2 gene that results in the amino acid substitution of Lysine for glutamic at codon 200 … (more)
A homozygous missense variation in exon 4 of the SRD5A2 gene that results in the amino acid substitution of Lysine for glutamic at codon 200 was detected. The observed variant c.598G>A (p.Glu200Lys) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by SIFT. The reference codon is conserved across species. (less)
Clinical Features:
Androgen insufficiency (absent) , Congenital adrenal hypoplasia (present)
Age: 0-9 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
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Pathogenic
(Aug 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004038788.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: SRD5A2 c.595G>A (p.Glu199Lys) results in a conservative amino acid change located in the C-terminal domain (IPR001104) of the encoded protein sequence. This variant … (more)
Variant summary: SRD5A2 c.595G>A (p.Glu199Lys) results in a conservative amino acid change located in the C-terminal domain (IPR001104) of the encoded protein sequence. This variant is also known as c.598G>A (p.Glu200Lys) in RefSeq NM_000348 and in the literature. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248858 control chromosomes (i.e., 6 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.595G>A has been reported in the literature in multiple individuals affected with 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (e.g., Anwar_1997, Arboleda_2013, Annamalai_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9208814, 22435390, 22362597). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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|
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Pathogenic
(Dec 18, 2023)
|
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: SCV001395940.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 200 of the SRD5A2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 200 of the SRD5A2 protein (p.Glu200Lys). This variant is present in population databases (rs756853742, gnomAD 0.02%). This missense change has been observed in individual(s) with ambiguous genitalia and/or steroid 5-alpha-reductase deficiency (PMID: 9208814; Invitae). ClinVar contains an entry for this variant (Variation ID: 492905). 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 expected to disrupt SRD5A2 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 26, 2012)
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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: SCV000692394.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
Comment:
Comment:
Variant summary: SRD5A2 c.595G>A (p.Glu199Lys) results in a conservative amino acid change located in the C-terminal domain (IPR001104) of the encoded protein sequence. This variant is also known as c.598G>A (p.Glu200Lys) in RefSeq NM_000348 and in the literature. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248858 control chromosomes (i.e., 6 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.595G>A has been reported in the literature in multiple individuals affected with 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (e.g., Anwar_1997, Arboleda_2013, Annamalai_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9208814, 22435390, 22362597). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 200 of the SRD5A2 protein (p.Glu200Lys). This variant is present in population databases (rs756853742, gnomAD 0.02%). This missense change has been observed in individual(s) with ambiguous genitalia and/or steroid 5-alpha-reductase deficiency (PMID: 9208814; Invitae). ClinVar contains an entry for this variant (Variation ID: 492905). 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 expected to disrupt SRD5A2 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Unknown function
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002564428.1
|
|
Comment:
A homozygous missense variation in exon 4 of the SRD5A2 gene that results in the amino acid substitution of Lysine for glutamic at codon 200 was detected. The observed variant c.598G>A (p.Glu200Lys) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by SIFT. The reference codon is conserved across species.
Comment:
Variant summary: SRD5A2 c.595G>A (p.Glu199Lys) results in a conservative amino acid change located in the C-terminal domain (IPR001104) of the encoded protein sequence. This variant is also known as c.598G>A (p.Glu200Lys) in RefSeq NM_000348 and in the literature. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248858 control chromosomes (i.e., 6 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.595G>A has been reported in the literature in multiple individuals affected with 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (e.g., Anwar_1997, Arboleda_2013, Annamalai_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9208814, 22435390, 22362597). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 200 of the SRD5A2 protein (p.Glu200Lys). This variant is present in population databases (rs756853742, gnomAD 0.02%). This missense change has been observed in individual(s) with ambiguous genitalia and/or steroid 5-alpha-reductase deficiency (PMID: 9208814; Invitae). ClinVar contains an entry for this variant (Variation ID: 492905). 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 expected to disrupt SRD5A2 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development. | Arboleda VA | Clinical genetics | 2013 | PMID: 22435390 |
| Puberty reveals a familial disorder of sex development. | Annamalai AK | Endocrine | 2012 | PMID: 22362597 |
| Male pseudohermaphroditism resulting from a novel mutation in the human steroid 5 alpha-reductase type 2 gene (SRD5A2). | Anwar R | Molecular pathology : MP | 1997 | PMID: 9208814 |
Text-mined citations for rs756853742 ...
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.