NM_000531.6(OTC):c.134T>G (p.Leu45Arg) AND Ornithine carbamoyltransferase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 26, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003040285.2

Allele description [Variation Report for NM_000531.6(OTC):c.134T>G (p.Leu45Arg)]

NM_000531.6(OTC):c.134T>G (p.Leu45Arg)

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.134T>G (p.Leu45Arg)

HGVS:

NC_000023.11:g.38367347T>G
NG_008471.1:g.19865T>G
NM_000531.6:c.134T>GMANE SELECT
NM_001407092.1:c.134T>G
NP_000522.3:p.Leu45Arg
NP_001394021.1:p.Leu45Arg
LRG_846t1:c.134T>G
LRG_846:g.19865T>G
LRG_846p1:p.Leu45Arg
NC_000023.10:g.38226600T>G

Protein change:

L45R

Molecular consequence:

NM_000531.6:c.134T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407092.1:c.134T>G - 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
SCV003350315	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 26, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 1671317, 30175132, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003350315

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 26, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

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

Mutation Study of Malaysian Patients with Ornithine Transcarbamylase Deficiency: Clinical, Molecular, and Bioinformatics Analyses of Two Novel Missense Mutations of the OTC Gene.

Ali EZ, Zakaria Y, Mohd Radzi MA, Ngu LH, Jusoh SA.

Biomed Res Int. 2018;2018:4320831. doi: 10.1155/2018/4320831.

PubMed [citation]

PMID:: 30175132
PMCID:: PMC6098936

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003350315.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 45 of the OTC protein (p.Leu45Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with OTC-related conditions (Invitae). 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. This variant disrupts the p.Leu45 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 1671317, 30175132), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Feb 20, 2024

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