ClinVar Genomic variation as it relates to human health
NM_000531.6(OTC):c.119G>A (p.Arg40His)
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.119G>A (p.Arg40His)
Variation ID: 11014 Accession: VCV000011014.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.4 X: 38367332 (GRCh38) [ NCBI UCSC ] X: 38226585 (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 Apr 4, 2013 Feb 14, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000531.6:c.119G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000522.3:p.Arg40His missense NC_000023.11:g.38367332G>A NC_000023.10:g.38226585G>A NG_008471.1:g.19850G>A LRG_846:g.19850G>A LRG_846t1:c.119G>A LRG_846p1:p.Arg40His P00480:p.Arg40His - Protein change
- R40H
- Other names
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- Canonical SPDI
- NC_000023.11:38367331: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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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 |
859 | 1011 |
Conditions - Germline
Condition
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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
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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 (7) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000011761.21 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 3, 2023 | RCV000083333.8 |
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
(Dec 07, 2017)
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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: SCV000854966.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
Number of individuals with the variant: 1
Sex: mixed
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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: SCV002033213.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(Jul 15, 2016)
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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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Counsyl
Accession: SCV000485682.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(May 25, 2017)
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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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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840025.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
The c.119G>A (p.Arg40His) variant was previously detected in several patients and families with OTC deficiency, males and females [PMID 21070677, 2095337, 7951259]. Among them, a … (more)
The c.119G>A (p.Arg40His) variant was previously detected in several patients and families with OTC deficiency, males and females [PMID 21070677, 2095337, 7951259]. Among them, a heterozygous female became symptomatic with hyperammenomia and acute decompensation at 13 years of age [PMID 21070677]. Additionally, a family with a hemizygous male and heterozygous sister also became symptomatic in their teenage years [PMID 2095337]. Their mother, also heterozygous, was asymptomatic but showed small orotic aciduria after protein loading. This variant has also been observed in our internal database in a 10 y/o patient with recent symptoms of OTC deficiency. Another change at the same amino acid location (p.Arg40Cys) has been reported but is considered a variant of unknown significance by our classification criteria at this time. This variant is not conserved in all mammals. Computer based prediction softwares yield discordant results regarding the pathogenicity of this change. This variant has not been observed in the ExAC database but has been detected in multiple patients and it is thus classified as pathogenic. (less)
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Pathogenic
(Apr 06, 2021)
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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: SCV000490962.2
First in ClinVar: Feb 20, 2014 Last updated: Apr 17, 2019 |
Comment:
Reported previously in association with a milder, later-onset ornithine transcarbamylase (OTC) deficiency phenotype in males as well as a late-onset, mild phenotype in heterozygous females … (more)
Reported previously in association with a milder, later-onset ornithine transcarbamylase (OTC) deficiency phenotype in males as well as a late-onset, mild phenotype in heterozygous females (Pinner et al. 2010; Cavicchi et al. 2014); Reported to be associated with 26-35% residual OTC enzyme activity when expressed in CHO cells (Augustin et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9175746, 17334707, 32995020, 32934962, 9048915, 25026867, 7951259, 11768581, 11260212, 8863155, 30449781, 28324312, 31447099, 11102556, 21070677, 33272297) (less)
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Likely pathogenic
(May 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026360.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PS4, PP3, PM2_SUP
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Pathogenic
(Jan 30, 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: SCV004040714.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Sep 07, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226706.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PP4, PM2, PM5, PS3
Number of individuals with the variant: 1
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Pathogenic
(Jan 25, 2024)
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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: SCV000945273.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 40 of the OTC protein (p.Arg40His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 40 of the OTC protein (p.Arg40His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 7951259, 19893582, 25026867). ClinVar contains an entry for this variant (Variation ID: 11014). 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%. Experimental studies have shown that this missense change affects OTC function (PMID: 11102556). This variant disrupts the p.Arg40 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7860066, 7951259, 19893582, 23209112, 25026867; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2001)
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no assertion criteria provided
Method: literature only
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ORNITHINE TRANSCARBAMYLASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031993.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
See 300461.0028 and Ploechl et al. (2001). Mavinakere et al. (2001) used (35)S labeling to study import and processing of OTC carrying the R40H mutation … (more)
See 300461.0028 and Ploechl et al. (2001). Mavinakere et al. (2001) used (35)S labeling to study import and processing of OTC carrying the R40H mutation in intact CHO cells and in isolated rat liver mitochondria compared to wildtype and OTC carrying an R141Q mutant that causes complete enzyme deficiency. OTC protein carrying the R40H mutation seemed to be imported and processed by the mitochondria in a manner similar to that of wildtype. However, it was consistently degraded to a smaller fragment in the intact cells, unlike the wildtype and R141Q mutant. The mature form of the enzyme was not susceptible to degradation. Mavinakere et al. (2001) concluded that deficiency in OTC enzymatic function conferred by the R40H mutation is likely caused by enhanced degradation of the preprotein in the cytosol. The authors further proposed that the variation in the rate of OTC turnover is responsible for the heterogeneity of the clinical phenotype in patients carrying this mutation. (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: SCV000115419.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
p.Arg40His, Late, CpG dinucleotide, expression studies show normal kinetics and thermal stability, protein degradation in cytosol
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Comment:
Converted during submission to Pathogenic.
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Pathogenic
(May 10, 2021)
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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: SCV002087161.1
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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Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity. | Lopes-Marques M | Human mutation | 2021 | PMID: 34015158 |
OTC deficiency in females: Phenotype-genotype correlation based on a 130-family cohort. | Gobin-Limballe S | Journal of inherited metabolic disease | 2021 | PMID: 34014569 |
Long-term outcomes in Ornithine Transcarbamylase deficiency: a series of 90 patients. | Brassier A | Orphanet journal of rare diseases | 2015 | PMID: 25958381 |
Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment. | Cavicchi C | Orphanet journal of rare diseases | 2014 | PMID: 25026867 |
Coagulopathy in patients with late-onset ornithine transcarbamylase deficiency in remission state: a previously unrecognized complication. | Ihara K | Pediatrics | 2013 | PMID: 23209112 |
Female heterozygotes for the hypomorphic R40H mutation can have ornithine transcarbamylase deficiency and present in early adolescence: a case report and review of the literature. | Pinner JR | Journal of medical case reports | 2010 | PMID: 21070677 |
Mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients have recurrently arisen and have been retained in some populations. | Numata S | Journal of human genetics | 2010 | PMID: 19893582 |
Paternal transmission and slow elimination of mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients. | Numata S | Journal of human genetics | 2008 | PMID: 18030415 |
Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential. | Arranz JA | Journal of inherited metabolic disease | 2007 | PMID: 17334707 |
Late-onset ornithine transcarbamylase deficiency in male patients: prognostic factors and characteristics of plasma amino acid profile. | Harada E | Pediatrics international : official journal of the Japan Pediatric Society | 2006 | PMID: 16635166 |
The clinically variable R40H mutant ornithine carbamoyltransferase shows cytosolic degradation of the precursor protein in CHO cells. | Mavinakere M | Journal of inherited metabolic disease | 2001 | PMID: 11768581 |
Late-onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon. | Ploechl E | Clinical genetics | 2001 | PMID: 11260212 |
Expression of wild-type and mutant human ornithine transcarbamylase genes in Chinese hamster ovary cells and lack of dominant negative effect of R141Q and R40H mutants. | Augustin L | Pediatric research | 2000 | PMID: 11102556 |
'Late onset' ornithine transcarbamylase deficiency: function of three purified recombinant mutant enzymes. | Morizono H | Human molecular genetics | 1997 | PMID: 9175746 |
The R40H mutation in a late onset type of human ornithine transcarbamylase deficiency in male patients. | Nishiyori A | Human genetics | 1997 | PMID: 9048915 |
Phenotypic variability in male patients carrying the mutant ornithine transcarbamylase (OTC) allele, Arg40His, ranging from a child with an unfavourable prognosis to an asymptomatic older adult. | Matsuda I | Journal of medical genetics | 1996 | PMID: 8863155 |
Ornithine transcarbamylase deficiency: new sites with increased probability of mutation. | Oppliger Leibundgut EO | Human genetics | 1995 | PMID: 7860066 |
Seven new mutations in the human ornithine transcarbamylase gene. | Tuchman M | Human mutation | 1994 | PMID: 7951259 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OTC | - | - | - | - |
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Text-mined citations for rs72554308 ...
HelpRecord last updated Feb 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.