Variant summary: OTC c.674C>T (p.Pro225Leu) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182904 control chromosomes (gnomAD). The variant, c.674C>T, has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (OTCD) (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000, Bijarnia-Mahay_2018). Hentzen_1991 reported this variant to segregate with OTCD in one family. These data indicate that the variant is very likely to be associated with disease. Several publications also reported (near) undetectable residual enzyme activities from patient samples (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic (1x) or pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000531.6(OTC):c.674C>T (p.Pro225Leu)
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.674C>T (p.Pro225Leu)
Variation ID: 11000 Accession: VCV000011000.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.4 X: 38408752 (GRCh38) [ NCBI UCSC ] X: 38268005 (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 Nov 1, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000531.6:c.674C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000522.3:p.Pro225Leu missense NC_000023.11:g.38408752C>T NC_000023.10:g.38268005C>T NG_008471.1:g.61270C>T LRG_846:g.61270C>T LRG_846t1:c.674C>T LRG_846p1:p.Pro225Leu P00480:p.Pro225Leu - Protein change
- P225L
- Other names
- -
- Canonical SPDI
- NC_000023.11:38408751: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
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 |
904 | 1057 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 1, 2022 | RCV000011747.21 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Nov 3, 2015 | RCV000083536.5 |
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
(Aug 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ornithine carbamoyltransferase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001364018.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: OTC c.674C>T (p.Pro225Leu) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. … (more)
Variant summary: OTC c.674C>T (p.Pro225Leu) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182904 control chromosomes (gnomAD). The variant, c.674C>T, has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (OTCD) (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000, Bijarnia-Mahay_2018). Hentzen_1991 reported this variant to segregate with OTCD in one family. These data indicate that the variant is very likely to be associated with disease. Several publications also reported (near) undetectable residual enzyme activities from patient samples (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic (1x) or pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Ornithine carbamoyltransferase deficiency
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002033227.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Pathogenic
(Nov 03, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000330994.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ornithine carbamoyltransferase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000825697.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individuals with ornithine transcarbamylase (OTC) deficiency (PMID: 1721894, 9286441, 9427144, 27070778). It has also been observed to segregate … (more)
This missense change has been observed in individuals with ornithine transcarbamylase (OTC) deficiency (PMID: 1721894, 9286441, 9427144, 27070778). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the OTC protein (p.Pro225Leu). ClinVar contains an entry for this variant (Variation ID: 11000). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro225 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 9427144, 10946359, 19669271), which suggests that this may be a clinically significant amino acid residue. 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. (less)
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Pathogenic
(Dec 01, 1991)
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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
|
OMIM
Accession: SCV000031979.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Hentzen et al. (1991) described a family in which a proband and his maternal uncle and maternal great-uncle died in the neonatal period with hyperammonemia … (more)
Hentzen et al. (1991) described a family in which a proband and his maternal uncle and maternal great-uncle died in the neonatal period with hyperammonemia caused by OTC deficiency (311250). The mother and maternal grandmother of the proband showed a dramatic increment of urinary orotic acid following protein load, confirming their status as carriers. Using PCR amplification of OTC-specific mRNA derived from a postmortem biopsy of the liver of the proband, Hentzen et al. (1991) found that the MspI site (CCGG) in exon 7 was abolished. They identified a C-T transition in the OTC gene, resulting in a pro225-to-leu (P225L) substitution. (less)
|
|
|
pathogenic
(-)
|
no assertion criteria provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
GenMed Metabolism Lab
Accession: SCV000115622.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
p.Pro225Leu, Neonatal
|
Comment:
Converted during submission to Pathogenic.
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|
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Likely pathogenic
(May 09, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Ornithine carbamoyltransferase deficiency
Affected status: no
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000268692.1
First in ClinVar: May 21, 2016 Last updated: May 21, 2016 |
Number of individuals with the variant: 1
Age: 20-29 years
Sex: female
Ethnicity/Population group: Persian
Geographic origin: Iran
|
Comment:
Comment:
This missense change has been observed in individuals with ornithine transcarbamylase (OTC) deficiency (PMID: 1721894, 9286441, 9427144, 27070778). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the OTC protein (p.Pro225Leu). ClinVar contains an entry for this variant (Variation ID: 11000). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro225 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 9427144, 10946359, 19669271), which suggests that this may be a clinically significant amino acid residue. 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.
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:
Variant summary: OTC c.674C>T (p.Pro225Leu) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182904 control chromosomes (gnomAD). The variant, c.674C>T, has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (OTCD) (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000, Bijarnia-Mahay_2018). Hentzen_1991 reported this variant to segregate with OTCD in one family. These data indicate that the variant is very likely to be associated with disease. Several publications also reported (near) undetectable residual enzyme activities from patient samples (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic (1x) or pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This missense change has been observed in individuals with ornithine transcarbamylase (OTC) deficiency (PMID: 1721894, 9286441, 9427144, 27070778). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the OTC protein (p.Pro225Leu). ClinVar contains an entry for this variant (Variation ID: 11000). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro225 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 9427144, 10946359, 19669271), which suggests that this may be a clinically significant amino acid residue. 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.
Comment:
Converted during submission to Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD). | Laemmle A | PloS one | 2016 | PMID: 27070778 |
| Acute fatal presentation of ornithine transcarbamylase deficiency in a previously healthy male. | Klein OD | Hepatology international | 2008 | PMID: 19669271 |
| Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. | McCullough BA | American journal of medical genetics | 2000 | PMID: 10946359 |
| Missense mutations in codon 225 of ornithine transcarbamylase (OTC) result in decreased amounts of OTC protein: a hypothesis on the molecular mechanism of the OTC deficiency. | García-Pérez MA | Journal of inherited metabolic disease | 1997 | PMID: 9427144 |
| The ornithine transcarbamylase (OTC) gene: mutations in 50 Japanese families with OTC deficiency. | Matsuda I | American journal of medical genetics | 1997 | PMID: 9286441 |
| Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene. | Hentzen D | Human genetics | 1991 | PMID: 1721894 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OTC | - | - | - | - |
Text-mined citations for rs67120076 ...
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.