ClinVar Genomic variation as it relates to human health
NM_000531.6(OTC):c.958C>T (p.Arg320Ter)
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_000531.6(OTC):c.958C>T (p.Arg320Ter)
Variation ID: 97371 Accession: VCV000097371.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.4 X: 38411952 (GRCh38) [ NCBI UCSC ] X: 38271205 (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 Feb 20, 2014 May 1, 2024 Aug 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000531.6:c.958C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000522.3:p.Arg320Ter nonsense NC_000023.11:g.38411952C>T NC_000023.10:g.38271205C>T NG_008471.1:g.64470C>T LRG_846:g.64470C>T LRG_846t1:c.958C>T LRG_846p1:p.Arg320Ter - Protein change
- R320*
- Other names
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- Canonical SPDI
- NC_000023.11:38411951: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.
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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
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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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OTC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
891 | 1043 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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 (1) |
no assertion criteria provided
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- | RCV000083620.3 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 17, 2023 | RCV000547443.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 21, 2020 | RCV002514462.2 |
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
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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
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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
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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
(Sep 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ornithine carbamoyltransferase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983511.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: OTC c.958C>T (p.Arg320X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: OTC c.958C>T (p.Arg320X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183266 control chromosomes. c.958C>T has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency (e.g. Gobin-Limballe_2021). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ornithine carbamoyltransferase deficiency
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002033232.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(Aug 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ornithine carbamoyltransferase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000631863.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This premature translational stop signal has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8829665, 9610619, 17041896, 25433810). This variant is not present in … (more)
This premature translational stop signal has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8829665, 9610619, 17041896, 25433810). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg320*) in the OTC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTC are known to be pathogenic (PMID: 10946359, 16786505). ClinVar contains an entry for this variant (Variation ID: 97371). 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
(Jul 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003551554.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.958C>T (p.R320*) alteration, located in coding exon 9 of the OTC gene, results from … (more)
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.958C>T (p.R320*) alteration, located in coding exon 9 of the OTC gene, results from a C to T substitution at nucleotide position 958. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 320. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of OTC, is not expected to trigger nonsense-mediated mRNA decay, and a truncated protein could still be expressed (Maquat, 2004). This alteration removes the last 35 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, this alteration and additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing. The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the OTC c.958C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.958C>T (p.R320*) alteration has been reported in multiple, unrelated male patients with OTC deficiency. Female carriers have been reported to be asymptomatic or present with a later onset OTC deficiency (Choi, 2015; Martín-Hernández, 2014; Matsuda, 1997; Rajabi, 2018; Yoo, 1996). Based on the available evidence, this alteration is classified as pathogenic. (less)
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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GenMed Metabolism Lab
Accession: SCV000115706.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
p.Arg320X, Neonatal
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Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Oct 22, 2020)
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no assertion criteria provided
Method: clinical testing
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Ornithine transcarbamylase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002087186.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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OTC deficiency in females: Phenotype-genotype correlation based on a 130-family cohort. | Gobin-Limballe S | Journal of inherited metabolic disease | 2021 | PMID: 34014569 |
Liver Failure as the Presentation of Ornithine Transcarbamylase Deficiency in a 13-Month-Old Female. | Rajabi F | JIMD reports | 2018 | PMID: 28887792 |
Clinical outcomes and the mutation spectrum of the OTC gene in patients with ornithine transcarbamylase deficiency. | Choi JH | Journal of human genetics | 2015 | PMID: 25994866 |
Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases. | Martín-Hernández E | Orphanet journal of rare diseases | 2014 | PMID: 25433810 |
Identification of novel mutations in the human ornithine transcarbamylase (OTC) gene of Korean patients with OTC deficiency and transient expression of the mutant proteins in vitro. | Kim GH | Human mutation | 2006 | PMID: 17041896 |
Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. | Yamaguchi S | Human mutation | 2006 | PMID: 16786505 |
Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. | McCullough BA | American journal of medical genetics | 2000 | PMID: 10946359 |
Prenatal molecular evaluation of six fetuses in four unrelated Korean families with ornithine transcarbamylase deficiency. | Yoo HW | Journal of Korean medical science | 1998 | PMID: 9610619 |
The ornithine transcarbamylase (OTC) gene: mutations in 50 Japanese families with OTC deficiency. | Matsuda I | American journal of medical genetics | 1997 | PMID: 9286441 |
Identification of new mutations in the ornithine transcarbamylase (OTC) gene in Korean families. | Yoo HW | Journal of inherited metabolic disease | 1996 | PMID: 8830175 |
A novel missense mutation in the exon containing the putative ornithine-binding domain of the OTC enzyme in a female. | Demmer LA | Human mutation | 1996 | PMID: 8829665 |
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Text-mined citations for rs72558473 ...
HelpRecord last updated May 01, 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.