This hemizygous mis-sense variant is identified in a 5 year male with recurrent episodes of lethargy, vomiting, fever, and seizures with encephalopathy and hyperamonemia (256 umol/L). Elder brother of the proband had died at 6 month of age due to encephalopathy. This nucleotide change is absent from the gnomAD database [PM2]. Insilico prediction predicts a deleterious nature of this variant, REVEL score: 0.91 [PP3]. A clinvar entry [Variation id: 11010] of this variant is already present with a "Pathogenic" interpretation [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic".
ClinVar Genomic variation as it relates to human health
NM_000531.6(OTC):c.386G>A (p.Arg129His)
Germline
Classification
Help
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.
(7)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000531.6(OTC):c.386G>A (p.Arg129His)
Variation ID: 11010 Accession: VCV000011010.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xp11.4 X: 38381429 (GRCh38) [ NCBI UCSC ] X: 38240682 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 19, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000531.6:c.386G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000522.3:p.Arg129His missense NC_000023.11:g.38381429G>A NC_000023.10:g.38240682G>A NG_008471.1:g.33947G>A LRG_846:g.33947G>A LRG_846t1:c.386G>A LRG_846p1:p.Arg129His P00480:p.Arg129His - Protein change
- R129H
- Other names
- -
- Canonical SPDI
- NC_000023.11:38381428:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| OTC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
903 | 1056 | |
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. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Oct 19, 2023 | RCV000011757.21 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV000083414.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Ornithine carbamoyltransferase deficiency
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002033218.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Pathogenic
(Oct 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ornithine carbamoyltransferase deficiency
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Accession: SCV004045988.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This hemizygous mis-sense variant is identified in a 5 year male with recurrent episodes of lethargy, vomiting, fever, and seizures with encephalopathy and hyperamonemia (256 … (more)
This hemizygous mis-sense variant is identified in a 5 year male with recurrent episodes of lethargy, vomiting, fever, and seizures with encephalopathy and hyperamonemia (256 umol/L). Elder brother of the proband had died at 6 month of age due to encephalopathy. This nucleotide change is absent from the gnomAD database [PM2]. Insilico prediction predicts a deleterious nature of this variant, REVEL score: 0.91 [PP3]. A clinvar entry [Variation id: 11010] of this variant is already present with a "Pathogenic" interpretation [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic". (less)
Sex: male
|
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ornithine carbamoyltransferase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004237385.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Apr 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ornithine carbamoyltransferase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001224329.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 11010). This missense change has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 7860064, 8081398, 8807340, 25853564, 29581464, 30285816; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 129 of the OTC protein (p.Arg129His). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. (less)
|
|
|
Pathogenic
(Jul 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001445889.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This variant has been previously reported as a hemizygous change in patients with ornithine transcarbamylase deficiency (PMID: 7860064, 8081398, 29581464, 30285816). Functional studies revealed that … (more)
This variant has been previously reported as a hemizygous change in patients with ornithine transcarbamylase deficiency (PMID: 7860064, 8081398, 29581464, 30285816). Functional studies revealed that patients carrying this variant in the hemizygous state had reductions of OTC activity to less that 5% of normal levels (PMID: 7860064, 8081398). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.386G>A (p.Arg129His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.386G>A (p.Arg129His) variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 1995)
|
no assertion criteria provided
Method: literature only
|
ORNITHINE TRANSCARBAMYLASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031989.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected patients from 2 Spanish families with OTC deficiency (311250), Garcia-Perez et al. (1995) identified an arg129-to-his (R129H) mutation in exon 4 of the … (more)
In affected patients from 2 Spanish families with OTC deficiency (311250), Garcia-Perez et al. (1995) identified an arg129-to-his (R129H) mutation in exon 4 of the OTC gene. The mutation results in the loss of a unique MspI restriction site that can be used for rapid diagnosis. The same mutation is found in the small spf-ash mouse, a rodent model of mild OTC deficiency, causing a neutral R129H mutation and inefficient splicing at the 5-prime donor site at the exon 4/intron 4 junction, with resultant 4 to 7% residual OTC activity. The mutation was found in the mother in one case, and arose de novo in the second case. Residual OTC activity, determined in a male and a female patient, was 1.3 and 3.5% of normal, respectively. Despite this low activity, the surviving patients had developed normally. One of them had reached reproductive age, raising the possibility of paternal transmission of the defect. (less)
|
|
|
pathogenic
(-)
|
no assertion criteria provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
GenMed Metabolism Lab
Accession: SCV000115500.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
p.Arg129His, Late, CpG dinucleotide, donor splice site error, identical to mutation in spfASH mouse
|
Comment:
Converted during submission to Pathogenic.
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 11010). This missense change has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 7860064, 8081398, 8807340, 25853564, 29581464, 30285816; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 129 of the OTC protein (p.Arg129His). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon.
Comment:
This variant has been previously reported as a hemizygous change in patients with ornithine transcarbamylase deficiency (PMID: 7860064, 8081398, 29581464, 30285816). Functional studies revealed that patients carrying this variant in the hemizygous state had reductions of OTC activity to less that 5% of normal levels (PMID: 7860064, 8081398). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.386G>A (p.Arg129His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.386G>A (p.Arg129His) variant is classified as Pathogenic.
Comment:
Converted during submission to Pathogenic.
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. |
Comment:
This hemizygous mis-sense variant is identified in a 5 year male with recurrent episodes of lethargy, vomiting, fever, and seizures with encephalopathy and hyperamonemia (256 umol/L). Elder brother of the proband had died at 6 month of age due to encephalopathy. This nucleotide change is absent from the gnomAD database [PM2]. Insilico prediction predicts a deleterious nature of this variant, REVEL score: 0.91 [PP3]. A clinvar entry [Variation id: 11010] of this variant is already present with a "Pathogenic" interpretation [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic".
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 11010). This missense change has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 7860064, 8081398, 8807340, 25853564, 29581464, 30285816; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 129 of the OTC protein (p.Arg129His). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon.
Comment:
This variant has been previously reported as a hemizygous change in patients with ornithine transcarbamylase deficiency (PMID: 7860064, 8081398, 29581464, 30285816). Functional studies revealed that patients carrying this variant in the hemizygous state had reductions of OTC activity to less that 5% of normal levels (PMID: 7860064, 8081398). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.386G>A (p.Arg129His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.386G>A (p.Arg129His) variant is classified as Pathogenic.
Comment:
Converted during submission to Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| OTC intron 4 variations mediate pathogenic splicing patterns caused by the c.386G>A mutation in humans and spf(ash) mice, and govern susceptibility to RNA-based therapies. | Sacchetto C | Molecular medicine (Cambridge, Mass.) | 2021 | PMID: 34906067 |
| Urea cycle disorders in India: clinical course, biochemical and genetic investigations, and prenatal testing. | Bijarnia-Mahay S | Orphanet journal of rare diseases | 2018 | PMID: 30285816 |
| Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea. | Tong W | Scientific reports | 2018 | PMID: 29581464 |
| Functional characterization of the spf/ash splicing variation in OTC deficiency of mice and man. | Rivera-Barahona A | PloS one | 2015 | PMID: 25853564 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia. | Gilbert-Dussardier B | Human mutation | 1996 | PMID: 8807340 |
| Demonstration of the spf-ash mutation in Spanish patients with ornithine transcarbamylase deficiency of moderate severity. | García-Pérez MA | Human genetics | 1995 | PMID: 7860064 |
| Four newly identified ornithine transcarbamylase (OTC) mutations (D126G, R129H, I172M and W332X) in Japanese male patients with early-onset OTC deficiency. | Matsuura T | Human mutation | 1994 | PMID: 8081398 |
| Seven new mutations in the human ornithine transcarbamylase gene. | Tuchman M | Human mutation | 1994 | PMID: 7951259 |
Text-mined citations for rs66656800 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.