NM_000531.6(OTC):c.119G>A (p.Arg40His) AND Ornithine carbamoyltransferase deficiency

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: May 29, 2024
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:: RCV000011761.24

Allele description [Variation Report for NM_000531.6(OTC):c.119G>A (p.Arg40His)]

NM_000531.6(OTC):c.119G>A (p.Arg40His)

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.119G>A (p.Arg40His)

HGVS:

NC_000023.11:g.38367332G>A
NG_008471.1:g.19850G>A
NM_000531.6:c.119G>AMANE SELECT
NP_000522.3:p.Arg40His
LRG_846t1:c.119G>A
LRG_846:g.19850G>A
LRG_846p1:p.Arg40His
NC_000023.10:g.38226585G>A
NM_000531.5:c.119G>A
P00480:p.Arg40His

Protein change:

R40H; ARG40HIS

Links:

UniProtKB: P00480#VAR_004846; OMIM: 300461.0029; dbSNP: rs72554308

NCBI 1000 Genomes Browser:

rs72554308

Molecular consequence:

NM_000531.6:c.119G>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
SCV000031993	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2001)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11260212, 11768581
SCV000485682	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Jul 15, 2016)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 7951259, 17334707, 11768581, 21070677, 25026867, 11260212, 9048915, 11102556, 9175746 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000840025	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000945273	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11102556, 7860066, 7951259, 19893582, 23209112, 25026867, 28492532
SCV002033213	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]
SCV002087161	Natera, Inc.	no assertion criteria provided	Pathogenic (May 10, 2021)	germline	clinical testing
SCV004040714	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 30, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005085998	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19893582, 25958381, 32934962, 25741868
SCV005184458	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 29, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 34014557, 11102556, 16635166 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	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	germline	no	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

Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential.

Arranz JA, Riudor E, Marco-Marín C, Rubio V.

J Inherit Metab Dis. 2007 Apr;30(2):217-26. Epub 2007 Mar 1.

PubMed [citation]

PMID:: 17334707

The clinically variable R40H mutant ornithine carbamoyltransferase shows cytosolic degradation of the precursor protein in CHO cells.

Mavinakere M, Morizono H, Shi D, Allewell NM, Tuchman M.

J Inherit Metab Dis. 2001 Nov;24(6):614-22.

PubMed [citation]

PMID:: 11768581

See all PubMed Citations (18)

Details of each submission

From OMIM, SCV000031993.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

See 300461.0028 and Ploechl et al. (2001).

Mavinakere et al. (2001) used (35)S labeling to study import and processing of OTC carrying the R40H mutation in intact CHO cells and in isolated rat liver mitochondria compared to wildtype and OTC carrying an R141Q mutant that causes complete enzyme deficiency. OTC protein carrying the R40H mutation seemed to be imported and processed by the mitochondria in a manner similar to that of wildtype. However, it was consistently degraded to a smaller fragment in the intact cells, unlike the wildtype and R141Q mutant. The mature form of the enzyme was not susceptible to degradation. Mavinakere et al. (2001) concluded that deficiency in OTC enzymatic function conferred by the R40H mutation is likely caused by enhanced degradation of the preprotein in the cytosol. The authors further proposed that the variation in the rate of OTC turnover is responsible for the heterogeneity of the clinical phenotype in patients carrying this mutation.

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

From Counsyl, SCV000485682.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840025.1

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

Description

The c.119G>A (p.Arg40His) variant was previously detected in several patients and families with OTC deficiency, males and females [PMID 21070677, 2095337, 7951259]. Among them, a heterozygous female became symptomatic with hyperammenomia and acute decompensation at 13 years of age [PMID 21070677]. Additionally, a family with a hemizygous male and heterozygous sister also became symptomatic in their teenage years [PMID 2095337]. Their mother, also heterozygous, was asymptomatic but showed small orotic aciduria after protein loading. This variant has also been observed in our internal database in a 10 y/o patient with recent symptoms of OTC deficiency. Another change at the same amino acid location (p.Arg40Cys) has been reported but is considered a variant of unknown significance by our classification criteria at this time. This variant is not conserved in all mammals. Computer based prediction softwares yield discordant results regarding the pathogenicity of this change. This variant has not been observed in the ExAC database but has been detected in multiple patients and it is thus 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000945273.4

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 40 of the OTC protein (p.Arg40His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 7951259, 19893582, 25026867). ClinVar contains an entry for this variant (Variation ID: 11014). 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%. Experimental studies have shown that this missense change affects OTC function (PMID: 11102556). This variant disrupts the p.Arg40 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7860066, 7951259, 19893582, 23209112, 25026867; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Genome-Nilou Lab, SCV002033213.1

#	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., SCV002087161.1

#	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, SCV004040714.1

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005085998.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ornithine transcarbamylase deficiency (MIM#311250). (I) 0109 - This gene is associated with X-linked disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In males, the phenotypic spectrum can range from lethal neonatal onset to milder forms in late childhood or adulthood while in heterozygous females, the phenotypic spectrum can range from asymptomatic to having recurrent hyperammonemia and/or neurologic impairment depending on the pattern of X-chromosome inactivation in the liver (OMIM, GeneReviews). In addition, individuals with pathogenic variants associated with mild, late-onset disease may experience severe hyperammonemia depending on exposure to strong environmental stressors (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Arg40Cys): 2 heterozygotes, 1 hemizygote, 0 homozygote). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated OTCace_N domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories (ClinVar). While this variant is commonly associated with milder, later-onset ornithine transcarbamylase deficiency, it has been reported in the context of severe early-onset disease, including one 7-day-old infant (PMIDs: 19893582, 25958381, 32934962). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005184458.1

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

Description

Variant summary: OTC c.119G>A (p.Arg40His) 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 183119 control chromosomes (gnomAD). c.119G>A has been reported in the literature in multiple individuals affected with ornithine transcarbamylase deficiency and several of these individuals had a late-onset presentation (example: Toquet_2020 , Harada_2006 ). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.118C>T, p.Arg40Cys), supporting the critical relevance of codon 40 to OTC protein function. In vitro and in vivo functional studies reveal reduced activity of the variant (Augustin_2000, Harada_2006). The following publications have been ascertained in the context of this evaluation (PMID: 34014557, 16635166, 11102556). ClinVar contains an entry for this variant (Variation ID: 11014). 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

Last Updated: Sep 29, 2024

Relating variation to medicine