ClinVar Genomic variation as it relates to human health
NM_000531.6(OTC):c.1061T>G (p.Phe354Cys)
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(2); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000531.6(OTC):c.1061T>G (p.Phe354Cys)
Variation ID: 97104 Accession: VCV000097104.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.4 X: 38421078 (GRCh38) [ NCBI UCSC ] X: 38280331 (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 Apr 20, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000531.6:c.1061T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000522.3:p.Phe354Cys missense NC_000023.11:g.38421078T>G NC_000023.10:g.38280331T>G NG_008471.1:g.73596T>G LRG_846:g.73596T>G LRG_846t1:c.1061T>G LRG_846p1:p.Phe354Cys P00480:p.Phe354Cys - Protein change
- F354C
- Other names
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- Canonical SPDI
- NC_000023.11:38421077:T:G
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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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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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
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
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Jul 27, 2023 | RCV000083329.7 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Dec 18, 2023 | RCV001095686.10 |
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
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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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Ornithine carbamoyltransferase deficiency
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251476.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The OTC c.1061T>G (p.F354C) variant was previously reported in mild ornithine transcarbamylase deficiency (PMID: 8857803; 16786505).
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 15, 2022)
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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: SCV002766071.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: OTC c.1061T>G (p.Phe354Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: OTC c.1061T>G (p.Phe354Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182812 control chromosomes. c.1061T>G has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in less than 2% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jul 27, 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: SCV001825855.4
First in ClinVar: Sep 08, 2021 Last updated: Sep 30, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9266388, 8857803, 28324312, 16786505, 32853555) (less)
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Pathogenic
(Sep 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ornithine carbamoyltransferase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004209063.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain Significance
(May 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ornithine carbamoyltransferase deficiency
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004833181.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces phenylalanine with cysteine at the last amino acid codon 354 of the OTC protein. Computational prediction suggests that this variant may … (more)
This missense variant replaces phenylalanine with cysteine at the last amino acid codon 354 of the OTC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a 13-year old boy diagnosed with late-onset ornithine transcarbamylase deficiency based on hyperammonemia and 1.8% residual OTC enzyme activity detected in his liver tissue frozen at autopsy (PMID: 8857803). This variant has been observed in a male with first presentation of hyperammonemia at age 14, as well as in his 55-year old, asymptomatic grandfather (PMID: 10946359). OTC enzyme activity was not determined in the proband. This variant has also been observed in a newborn girl diagnosed with phenylketonuria and unaffected with symptoms of ornithine transcarbamylase deficiency (PMID: 32853555). Her grandfather and younger male sibling were unaffected carriers of this variant. This variant has been identified in 1/182812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 18, 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: SCV003445216.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 354 of the OTC protein … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 354 of the OTC protein (p.Phe354Cys). This variant is present in population databases (rs72558495, gnomAD 0.001%). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 9266388, 10869432). ClinVar contains an entry for this variant (Variation ID: 97104). 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 OTC protein function with a positive predictive value of 95%. For these reasons, this variant has been 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: SCV000115415.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
p.Phe354Cys, Late
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Comment:
Converted during submission to Pathogenic.
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Likely pathogenic
(Aug 03, 2017)
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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: SCV002087188.1
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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Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project. | Roman TS | American journal of human genetics | 2020 | PMID: 32853555 |
Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. | Yamaguchi S | Human mutation | 2006 | PMID: 16786505 |
Mutations and polymorphisms in the human ornithine transcarbamylase gene. | Tuchman M | Human mutation | 2002 | PMID: 11793468 |
Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. | McCullough BA | American journal of medical genetics | 2000 | PMID: 10946359 |
In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle. | Lee B | Proceedings of the National Academy of Sciences of the United States of America | 2000 | PMID: 10869432 |
Identification of 'private' mutations in patients with ornithine transcarbamylase deficiency. | Tuchman M | Journal of inherited metabolic disease | 1997 | PMID: 9266388 |
Vomiting, ataxia, and altered mental status in an adolescent: late-onset ornithine transcarbamylase deficiency. | Myers JH | The American journal of emergency medicine | 1996 | PMID: 8857803 |
Text-mined citations for rs72558495 ...
HelpRecord last updated Apr 20, 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.