NM_000531.6(OTC):c.275G>A (p.Arg92Gln) AND Ornithine carbamoyltransferase deficiency

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Dec 10, 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:: RCV000990783.13

Allele description [Variation Report for NM_000531.6(OTC):c.275G>A (p.Arg92Gln)]

NM_000531.6(OTC):c.275G>A (p.Arg92Gln)

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.275G>A (p.Arg92Gln)

HGVS:

NC_000023.11:g.38369854G>A
NG_008471.1:g.22372G>A
NM_000531.6:c.275G>AMANE SELECT
NP_000522.3:p.Arg92Gln
LRG_846t1:c.275G>A
LRG_846:g.22372G>A
LRG_846p1:p.Arg92Gln
NC_000023.10:g.38229107G>A
NM_000531.5:c.275G>A
P00480:p.Arg92Gln

Protein change:

R92Q

Links:

UniProtKB: P00480#VAR_004865; dbSNP: rs66550389

NCBI 1000 Genomes Browser:

rs66550389

Molecular consequence:

NM_000531.6:c.275G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001141819	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001214613	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 10, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1671317, 19138872, 26753873, 30285816, 28492532
SCV001984829	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002033215	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]
SCV002087165	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 27, 2021)	germline	clinical testing
SCV003835905	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 27, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Improved molecular diagnostics for ornithine transcarbamylase deficiency.

Grompe M, Caskey CT, Fenwick RG.

Am J Hum Genet. 1991 Feb;48(2):212-22.

PubMed [citation]

PMID:: 1671317
PMCID:: PMC1683033

High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH.

Shchelochkov OA, Li FY, Geraghty MT, Gallagher RC, Van Hove JL, Lichter-Konecki U, Fernhoff PM, Copeland S, Reimschisel T, Cederbaum S, Lee B, Chinault AC, Wong LJ.

Mol Genet Metab. 2009 Mar;96(3):97-105. doi: 10.1016/j.ymgme.2008.11.167. Epub 2009 Jan 12.

PubMed [citation]

PMID:: 19138872

See all PubMed Citations (6)

Details of each submission

From Mendelics, SCV001141819.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001214613.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 92 of the OTC protein (p.Arg92Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 1671317, 19138872, 26753873, 30285816). ClinVar contains an entry for this variant (Variation ID: 97152). 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%. 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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001984829.1

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

Description

This variant has been previously reported as a hemizygous change in patients with ornithine transcarbamylase deficiency (PMID: 1671317, 26753873, 30285816). It is absent from the gnomAD population database and thus is presumed to be rare. The c.275G>A (p.Arg92Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.275G>A (p.Arg92Gln) variant is classified as Pathogenic.

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

From Genome-Nilou Lab, SCV002033215.1

#	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., SCV002087165.1

#	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

From Baylor Genetics, SCV003835905.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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