NM_000531.6(OTC):c.626C>T (p.Ala209Val) AND Ornithine carbamoyltransferase deficiency

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 27, 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:: RCV000634844.10

Allele description [Variation Report for NM_000531.6(OTC):c.626C>T (p.Ala209Val)]

NM_000531.6(OTC):c.626C>T (p.Ala209Val)

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.626C>T (p.Ala209Val)

HGVS:

NC_000023.11:g.38403703C>T
NG_008471.1:g.56221C>T
NM_000531.6:c.626C>TMANE SELECT
NP_000522.3:p.Ala209Val
LRG_846t1:c.626C>T
LRG_846:g.56221C>T
LRG_846p1:p.Ala209Val
NC_000023.10:g.38262956C>T
NM_000531.5:c.626C>T
P00480:p.Ala209Val

Protein change:

A209V

Links:

UniProtKB: P00480#VAR_004909; dbSNP: rs72558417

NCBI 1000 Genomes Browser:

rs72558417

Molecular consequence:

NM_000531.6:c.626C>T - 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
SCV000756193	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 27, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11793468, 8530002, 8807340, 9286441, 10070627, 12536032, 25433810, 28492532
SCV001572479	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 12, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25433810, 8530002, 8807340, 12536032, 10070627, 9686344, 32934962 Citation Link,
SCV002033225	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]
SCV003927817	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	no assertion criteria provided	Pathogenic (Apr 1, 2023)	germline	clinical testing

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

Citations

PubMed

Mutations and polymorphisms in the human ornithine transcarbamylase gene.

Tuchman M, Jaleel N, Morizono H, Sheehy L, Lynch MG.

Hum Mutat. 2002 Feb;19(2):93-107. Review.

PubMed [citation]

PMID:: 11793468

The ornithine transcarbamylase (OTC) gene: mutations in 50 Japanese families with OTC deficiency.

Matsuda I, Tanase S.

Am J Med Genet. 1997 Sep 5;71(4):378-83. Review.

PubMed [citation]

PMID:: 9286441

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000756193.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 209 of the OTC protein (p.Ala209Val). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects OTC function (PMID: 8807340, 11793468). 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. ClinVar contains an entry for this variant (Variation ID: 97275). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8530002, 8807340, 9286441, 10070627, 12536032, 25433810). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).

#	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, SCV001572479.1

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

Description

Variant summary: OTC c.626C>T (p.Ala209Val) 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 183102 control chromosomes. c.626C>T has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (e.g. Garcia-Perez_1995, Gilbert-Dussardier_1996, Popowska_1999, Kurihara_2003, Martin-Hernandez_2014, Zhou_2020). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence indicating severely reduced OTC enzyme activity in patient cells with the variant (e.g. Garcia-Perez_1995, Gilbert-Dussardier_1996). One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited 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, SCV002033225.1

#	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 Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), SCV003927817.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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