This variant was classified as: Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000531.6(OTC):c.540+265G>A
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000531.6(OTC):c.540+265G>A
Variation ID: 449382 Accession: VCV000449382.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.4 X: 38401693 (GRCh38) [ NCBI UCSC ] X: 38260946 (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 Dec 19, 2017 Nov 10, 2024 Oct 7, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000531.6:c.540+265G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000023.11:g.38401693G>A NC_000023.10:g.38260946G>A NG_008471.1:g.54211G>A LRG_846:g.54211G>A LRG_846t1:c.540+265G>A - Protein change
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- Other names
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- Canonical SPDI
- NC_000023.11:38401692: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
Help
The frequency of the allele represented by this VCV record.
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- 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 | ||
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| 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. |
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| OTC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
913 | 1066 | |
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 (1) |
criteria provided, single submitter
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Mar 22, 2022 | RCV000521922.2 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Oct 7, 2024 | RCV000548908.18 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626698.2 |
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
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
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Abnormal circulating ornithine concentration
Hyperammonemia Protein avoidance
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747401.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Ornithine carbamoyltransferase deficiency
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368080.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic.
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Pathogenic
(May 04, 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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Mendelics
Accession: SCV002517834.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Nov 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ornithine carbamoyltransferase deficiency
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581227.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4_MOD, PM6, PM2_SUP, PP4
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Mar 08, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004357050.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported … (more)
This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Sep 21, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000631860.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 449382). This variant has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 18204299, 18440262, 33489762). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change falls in intron 5 of the OTC gene. It does not directly change the encoded amino acid sequence of the OTC protein. (less)
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Pathogenic
(Jul 19, 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: SCV004834032.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported … (more)
This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
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Pathogenic
(Oct 07, 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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806270.2
First in ClinVar: Apr 06, 2024 Last updated: Oct 20, 2024 |
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Pathogenic
(Mar 22, 2022)
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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: SCV000617478.3
First in ClinVar: Dec 19, 2017 Last updated: Nov 10, 2024 |
Comment:
Non-canonical splice site variant demonstrated to result in loss of normal function through nonsense-mediated mRNA decay (Ogino et al. 2007; Engel et al. 2008); No … (more)
Non-canonical splice site variant demonstrated to result in loss of normal function through nonsense-mediated mRNA decay (Ogino et al. 2007; Engel et al. 2008); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 18440262, 34014569, 19823873, 28771251, 33272297, 33489762, 18204299) (less)
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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: SCV001458517.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 449382). This variant has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 18204299, 18440262, 33489762). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change falls in intron 5 of the OTC gene. It does not directly change the encoded amino acid sequence of the OTC protein.
Comment:
This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Non-canonical splice site variant demonstrated to result in loss of normal function through nonsense-mediated mRNA decay (Ogino et al. 2007; Engel et al. 2008); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 18440262, 34014569, 19823873, 28771251, 33272297, 33489762, 18204299)
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 variant was classified as: Pathogenic.
Comment:
This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 449382). This variant has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 18204299, 18440262, 33489762). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change falls in intron 5 of the OTC gene. It does not directly change the encoded amino acid sequence of the OTC protein.
Comment:
This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Non-canonical splice site variant demonstrated to result in loss of normal function through nonsense-mediated mRNA decay (Ogino et al. 2007; Engel et al. 2008); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 18440262, 34014569, 19823873, 28771251, 33272297, 33489762, 18204299)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| OTC deficiency in females: Phenotype-genotype correlation based on a 130-family cohort. | Gobin-Limballe S | Journal of inherited metabolic disease | 2021 | PMID: 34014569 |
| A deep intronic variant is a common cause of OTC deficiency in individuals with previously negative genetic testing. | Kumar RD | Molecular genetics and metabolism reports | 2021 | PMID: 33489762 |
| Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency. | Engel K | Molecular genetics and metabolism | 2008 | PMID: 18440262 |
| Mutation analysis of the ornithine transcarbamylase (OTC) gene in five Japanese OTC deficiency patients revealed two known and three novel mutations including a deep intronic mutation. | Ogino W | The Kobe journal of medical sciences | 2007 | PMID: 18204299 |
Text-mined citations for rs1555975756 ...
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 Nov 10, 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.