ClinVar Genomic variation as it relates to human health
NM_000531.6(OTC):c.118C>T (p.Arg40Cys)
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.118C>T (p.Arg40Cys)
Variation ID: 11013 Accession: VCV000011013.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.4 X: 38367331 (GRCh38) [ NCBI UCSC ] X: 38226584 (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 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000531.6:c.118C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000522.3:p.Arg40Cys missense NC_000023.11:g.38367331C>T NC_000023.10:g.38226584C>T NG_008471.1:g.19849C>T LRG_846:g.19849C>T LRG_846t1:c.118C>T LRG_846p1:p.Arg40Cys P00480:p.Arg40Cys - Protein change
- R40C
- Other names
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- Canonical SPDI
- NC_000023.11:38367330: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 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
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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
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/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Dec 27, 2023 | RCV000011760.20 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Feb 13, 2023 | RCV000083332.2 |
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
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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Pathogenic
(Jun 15, 2020)
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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: SCV001372246.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: OTC c.118C>T (p.Arg40Cys) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyl transferase, carbamoyl-P binding domain (IPR006132) of the encoded … (more)
Variant summary: OTC c.118C>T (p.Arg40Cys) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyl transferase, carbamoyl-P binding domain (IPR006132) of 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 1.1e-05 in 183119 control chromosomes. c.118C>T has been reported in the literature in individuals affected with later onset Ornithine Transcarbamylase Deficiency and has subsequently cited by others (example, Oppliger Leibundgut_1995, Ploechl_2001, Thurlow_2010, Cavicchi_2014, Caldovic_2015, Ihara_2012). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal OTC activity (Oppliger Leibundgut_1995). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Lastly, another variant at this codon, p.Arg40His has been reported in patients with OTC deficiency supporting the functional relevance of this residue. Based on the evidence outlined above, the variant was classified as pathogenic for fatal late-onset OTC deficiency in boys. (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: SCV002033212.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely Pathogenic
(Jun 24, 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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847947.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg40Cys variant in OTC has been previously reported in at least 2 hemizygous males with clinical features of late onset ornithine transcarbamylase (OTC) deficiency … (more)
The p.Arg40Cys variant in OTC has been previously reported in at least 2 hemizygous males with clinical features of late onset ornithine transcarbamylase (OTC) deficiency (Oppliger Leibundgut 1995 PMID: 7860066, Ploechl 2001 PMID: 11260212, Thurlow 2010 PMID: 20406775). The variant was also identified in one of the affected male's affected sibling and their mother (obligate carrier). Both affected brothers had very minimal to no OTC enzyme activity as measured from liver biopsies (Oppliger Leibundgut 1995 PMID: 7860066, Ploechl 2001 PMID: 11260212). This variant has been reported in ClinVar (Variation ID 11013) and has been identified in 0.003% (3/92405) of European chromosomes by gnomAD, including 1 hemizygote (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Another variant at the same position, p.Arg40His, has been reported in several probands with features of OTC deficiency is also classified in ClinVar by other clinical laboratories as pathogenic or likely pathogenic (Variation ID 11014). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for X-Linked OTC deficiency. ACMG/AMP criteria applied: PS4_Moderate, PP1, PS3_Supporting, PP3, PM5_Supporting. (less)
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Likely pathogenic
(Oct 31, 2018)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893833.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ornithine carbamoyltransferase deficiency
(X-linked recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768001.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. The following criteria are met: 0102 - Loss of function is a known … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ornithine transcarbamylase (OTC) deficiency (MIM#311250). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (2 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain (Pfam). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg40Leu) has previously been reported in an adult male OTC deficiency patient (PMID: 25026867). In addition, p.(Arg40His) has also been reported in at least 10 OTC deficiency patients and has been suggested to result in a milder phenotype then p.(Arg40Cys) (ClinVar, PMID: 25026867; 11260212; 32995020; 19893582). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least eight individuals and is consistently reported as a fatal late childhood/adulthood onset form of ornithine transcarbamylase deficiency (ClinVar; PMID: 7860066; 20406775; 11260212; 27738433). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Feb 13, 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: SCV003805345.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23209112, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23209112, 28324312, 8863155, 9143919, 20406775, 21070677, 11793468, 11260212, 7860066, 8364586, 25026867, 34014569, 35046116) (less)
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Pathogenic
(Dec 27, 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: SCV000756189.7
First in ClinVar: Jan 30, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 40 of the OTC protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 40 of the OTC protein (p.Arg40Cys). This variant is present in population databases (rs72554307, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with clinical features of ornithine transcarbamylase deficiency (PMID: 7860066, 11260212, 23209112; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11013). 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%. 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: 7951259, 19893582, 25026867). 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
(-)
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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: SCV000115418.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
p.Arg40Cys, Late, CpG dinucleotide
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Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Feb 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: SCV000031992.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 30, 2017 |
Comment on evidence:
Ploechl et al. (2001) reported on late-onset OTC deficiency (311250) in 2 families with mutations in the same codon, but with different base substitutions. Onset … (more)
Ploechl et al. (2001) reported on late-onset OTC deficiency (311250) in 2 families with mutations in the same codon, but with different base substitutions. Onset of symptoms showed great variation, and clinical diagnosis was late and difficult. In family A, with a C-T transition causing an arg40-to-cys (R40C) substitution in the OTC gene, hemizygous males died at ages 12 and 18 years. In family B, with a G-A transition causing an arg40-to-his (R40H) substitution (300461.0029), hemizygous males died at ages 20, 26, and 30 years. Whereas the R40C mutation is a private one, as in most cases of OTC deficiency, the R40H mutation is a recurrent one found first by Tuchman et al. (1994), and subsequently by Oppliger Leibundgut et al. (1995) and Matsuda et al. (1996). (less)
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Likely pathogenic
(Sep 16, 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: SCV001458515.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults. | Hidaka M | Acute medicine & surgery | 2020 | PMID: 32995020 |
Hyperammonemia: What Urea-lly Need to Know: Case Report of Severe Noncirrhotic Hyperammonemic Encephalopathy and Review of the Literature. | Upadhyay R | Case reports in medicine | 2016 | PMID: 27738433 |
Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. | Caldovic L | Journal of genetics and genomics = Yi chuan xue bao | 2015 | PMID: 26059767 |
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 |
Fatal ammonia toxicity in an adult due to an undiagnosed urea cycle defect: under-recognition of ornithine transcarbamylase deficiency. | Thurlow VR | Annals of clinical biochemistry | 2010 | PMID: 20406775 |
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 |
Late-onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon. | Ploechl E | Clinical genetics | 2001 | PMID: 11260212 |
Ornithine transcarbamylase deficiency: ten new mutations and high proportion of de novo mutations in heterozygous females. | Oppliger Leibundgut E | Human mutation | 1997 | PMID: 9143919 |
Ornithine transcarbamylase deficiency: characterization of gene mutations and polymorphisms. | Oppliger Leibundgut EO | Human mutation | 1996 | PMID: 8956038 |
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 |
Mutations and polymorphisms in the human ornithine transcarbamylase gene. | Tuchman M | Human mutation | 1993 | PMID: 8364586 |
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Text-mined citations for rs72554307 ...
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.