NM_000531.6(OTC):c.958C>T (p.Arg320Ter) AND Ornithine carbamoyltransferase deficiency

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000547443.11

Allele description [Variation Report for NM_000531.6(OTC):c.958C>T (p.Arg320Ter)]

NM_000531.6(OTC):c.958C>T (p.Arg320Ter)

Gene:

OTC:ornithine transcarbamylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.4

Genomic location:

Preferred name:

NM_000531.6(OTC):c.958C>T (p.Arg320Ter)

HGVS:

NC_000023.11:g.38411952C>T
NG_008471.1:g.64470C>T
NM_000531.6:c.958C>TMANE SELECT
NP_000522.3:p.Arg320Ter
LRG_846t1:c.958C>T
LRG_846:g.64470C>T
LRG_846p1:p.Arg320Ter
NC_000023.10:g.38271205C>T
NM_000531.5:c.958C>T

Protein change:

R320*

Links:

dbSNP: rs72558473

NCBI 1000 Genomes Browser:

rs72558473

Molecular consequence:

NM_000531.6:c.958C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Ornithine carbamoyltransferase deficiency (OTCD)
Synonyms:: ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO; Ornithine transcarbamylase deficiency; OTC deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010703; MedGen: C0268542; Orphanet: 664; OMIM: 311250

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000631863	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 17, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8829665, 9610619, 17041896, 25433810, 10946359, 16786505, 28492532
SCV001983511	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 28, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002033232	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002087186	Natera, Inc.	no assertion criteria provided	Pathogenic (Oct 22, 2020)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel missense mutation in the exon containing the putative ornithine-binding domain of the OTC enzyme in a female.

Demmer LA, Kim JM, de Martinville B, Dowton SB.

Hum Mutat. 1996;7(3):279. No abstract available.

PubMed [citation]

PMID:: 8829665

Prenatal molecular evaluation of six fetuses in four unrelated Korean families with ornithine transcarbamylase deficiency.

Yoo HW, Kim GH.

J Korean Med Sci. 1998 Apr;13(2):179-85.

PubMed [citation]

PMID:: 9610619
PMCID:: PMC3054473

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000631863.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This premature translational stop signal has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8829665, 9610619, 17041896, 25433810). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg320*) in the OTC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTC are known to be pathogenic (PMID: 10946359, 16786505). ClinVar contains an entry for this variant (Variation ID: 97371). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001983511.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: OTC c.958C>T (p.Arg320X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183266 control chromosomes. c.958C>T has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency (e.g. Gobin-Limballe_2021). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002033232.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002087186.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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