ClinVar Genomic variation as it relates to human health
NM_024592.5(SRD5A3):c.57G>A (p.Trp19Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024592.5(SRD5A3):c.57G>A (p.Trp19Ter)
Variation ID: 96125 Accession: VCV000096125.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q12 4: 55346393 (GRCh38) [ NCBI UCSC ] 4: 56212560 (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 Dec 19, 2017 Feb 28, 2024 Feb 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024592.5:c.57G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078868.1:p.Trp19Ter nonsense NC_000004.12:g.55346393G>A NC_000004.11:g.56212560G>A NG_028230.1:g.5173G>A - Protein change
- W19*
- Other names
- p.Trp19Ter
- Canonical SPDI
- NC_000004.12:55346392:G:A
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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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00012
1000 Genomes Project 30x 0.00031
Exome Aggregation Consortium (ExAC) 0.00036
1000 Genomes Project 0.00040
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 | ||
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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
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. |
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SRD5A3 | - | - |
GRCh38 GRCh37 |
105 | 247 |
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. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000082197.16 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 12, 2020 | RCV000173528.13 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001003586.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814055.1 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jul 8, 2016 | RCV000851211.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 9, 2024 | RCV001542529.3 |
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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Pathogenic
(Jul 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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SRD5A3-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences
Accession: SCV000693886.1
First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018 |
Number of individuals with the variant: 1
Clinical Features:
Abnormal isoelectric focusing of serum transferrin (present) , Failure to thrive (present) , Visual impairment (present) , Optic nerve hypoplasia (present) , Coloboma (present) , … (more)
Abnormal isoelectric focusing of serum transferrin (present) , Failure to thrive (present) , Visual impairment (present) , Optic nerve hypoplasia (present) , Coloboma (present) , Nystagmus (present) , Pituitary gland hypoplasia (present) , Polymicrogyria (present) , Cerebellar vermis hypoplasia (present) , Ichthyosiform abnormality of the skin (present) , Hypertrichosis (present) , Hyperpigmentation (present) , Sarcal lesion (present) , microcephaly (present) , Brachycephaly (present) , Hypertelorism (present) , Low-set ears (present) , Depressed nasal bridge (present) , Beaked nose (present) , Cleft palate (present) , Low insulin growth factor 1 (present) , Antithrombin III deficiency (present) , Duplicated left renal pelvis (present) (less)
Family history: no
Age: 0-9 years
Sex: male
Geographic origin: United Arab Emirates
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Kahrizi syndrome
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760137.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755148.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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SRD5A3-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000807621.2
First in ClinVar: Mar 20, 2018 Last updated: Dec 11, 2022 |
Comment:
This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 5-year-old male with intellectual disability, hypotonia, ataxia, … (more)
This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 5-year-old male with intellectual disability, hypotonia, ataxia, abnormal movements, dysmorphic features, microcephaly, failure to thrive, optic nerve atrophy, and a duplicated left kidney. Heterozygotes are expected to be asymptomatic carriers (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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SRD5A3-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820084.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The stop gained p.W19* in SRD5A3 (NM_024592.4) has been reported in the homozygous state in affected patients(Morava et al., 2010;Gupta N et al,2018) . The … (more)
The stop gained p.W19* in SRD5A3 (NM_024592.4) has been reported in the homozygous state in affected patients(Morava et al., 2010;Gupta N et al,2018) . The variant has been classified as Pathogenic in the ClinVar database. It is observed in heterozygous state in 21/26490 (0.0793%) alleles from individuals of South Asian background in the gnomAD dataset.This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Generalized hypotonia (present) , Macrocephaly (present) , Persistent head lag (present) , Reduced visual acuity (present) , Rotary nystagmus (present) … (more)
Global developmental delay (present) , Generalized hypotonia (present) , Macrocephaly (present) , Persistent head lag (present) , Reduced visual acuity (present) , Rotary nystagmus (present) , Depressed nasal bridge (present) , Gingival overgrowth (present) (less)
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Pathogenic
(Feb 14, 2023)
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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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GeneDx
Accession: SCV000322373.8
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29998879, 33879512, 34758253, 32581362, 24433453, 22304929, 20852264, 27480077, 28253385, 28940310, 28771251, 27457812, 25326635, 30315573, 30653986, 31980526, 31319225, 35725860) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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SRD5A3-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003925472.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
A Heterozygous Nonsense variant c.57G>A in Exon 1 of the SRD5A3 gene that results in the amino acid substitution p.Trp19* was identified. The observed variant … (more)
A Heterozygous Nonsense variant c.57G>A in Exon 1 of the SRD5A3 gene that results in the amino acid substitution p.Trp19* was identified. The observed variant has a minimum allele frequency of 0.00012/% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID 96125). This variant has been observed in many individuals affected with Congenital disorder of glycosylation reported by Bastaki F et al., 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Nov 12, 2020)
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criteria provided, single submitter
Method: clinical testing
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SRD5A3-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002203439.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with SRD5A3-congenital disorder of glycosylation (PMID: 24433453, 28940310, … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with SRD5A3-congenital disorder of glycosylation (PMID: 24433453, 28940310, 20852264). ClinVar contains an entry for this variant (Variation ID: 96125). This variant is present in population databases (rs398124401, ExAC 0.1%). This sequence change creates a premature translational stop signal (p.Trp19*) in the SRD5A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SRD5A3 are known to be pathogenic (PMID: 20637498, 20700148, 31638560). (less)
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Pathogenic
(Jan 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000224649.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 8
Sex: mixed
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021961.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Kahrizi syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV004565365.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
A heterozygous nonsense variant in exon 1 of the SRD5A3 gene that results in a stop codon and premature truncation of the protein at codon … (more)
A heterozygous nonsense variant in exon 1 of the SRD5A3 gene that results in a stop codon and premature truncation of the protein at codon 19 (p.Trp19Ter) was detected. The observed variant has previously been reported in patients affected with cerebello-ocular syndrome with abnormal glycosylation [PMID: 20852264]. The p.Trp19Ter variant has a minor allele frequency of 0.03%, 0.005%, 0.01% and 0.002% in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases respectively. The in-silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Global developmental delay (absent) , Proptosis (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 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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Likely pathogenic
(Jul 08, 2016)
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no assertion criteria provided
Method: research
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Congenital Disorder of Glycosylation
Affected status: yes
Allele origin:
unknown
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000993462.1
First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Cone-rod dystrophy
Autism Global developmental delay
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001161963.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
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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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Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Review of SRD5A3 Disease-Causing Sequence Variants and Ocular Findings in Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation, and a Detailed New Case. | Kousal B | Folia biologica | 2019 | PMID: 31638560 |
Single-center experience of N-linked Congenital Disorders of Glycosylation with a Summary of Molecularly Characterized Cases in Arabs. | Bastaki F | Annals of human genetics | 2018 | PMID: 28940310 |
SRD5A3-CDG: Expanding the phenotype of a congenital disorder of glycosylation with emphasis on adult onset features. | Wheeler PG | American journal of medical genetics. Part A | 2016 | PMID: 27480077 |
Adult phenotype and further phenotypic variability in SRD5A3-CDG. | Kara B | BMC medical genetics | 2014 | PMID: 24433453 |
Life with too much polyprenol: polyprenol reductase deficiency. | Gründahl JE | Molecular genetics and metabolism | 2012 | PMID: 22304929 |
Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3. | Kahrizi K | European journal of human genetics : EJHG | 2011 | PMID: 20700148 |
A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. | Morava E | Brain : a journal of neurology | 2010 | PMID: 20852264 |
SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. | Cantagrel V | Cell | 2010 | PMID: 20637498 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SRD5A3 | - | - | - | - |
Text-mined citations for rs398124401 ...
HelpRecord last updated Apr 06, 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.