NM_000531.6(OTC):c.119G>A (p.Arg40His) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: May 3, 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:: RCV000083333.8

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000115419	GenMed Metabolism Lab	no assertion criteria provided	pathogenic	unknown	not provided	PubMed (1) [See all records that cite this PMID]
SCV000490962	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 6, 2021)	germline	clinical testing	Citation Link,
SCV000854966	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 7, 2017)	germline	clinical testing	Citation Link,
SCV004026360	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004226706	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 7, 2022)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 11102556, 11768581, 16635166, 18030415, 21070677, 25958381, 34014569, 34015158, 7951259, 8863155, 9048915, 25741868

Description

p.Arg40His, Late, CpG dinucleotide, expression studies show normal kinetics and thermal stability, protein degradation in cytosol: SCV000115419

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	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Expression of wild-type and mutant human ornithine transcarbamylase genes in Chinese hamster ovary cells and lack of dominant negative effect of R141Q and R40H mutants.

Augustin L, Mavinakere M, Morizono H, Tuchman M.

Pediatr Res. 2000 Dec;48(6):842-6.

PubMed [citation]

PMID:: 11102556

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 (12)

Details of each submission

From GenMed Metabolism Lab, SCV000115419.1

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

Description

Converted during submission to Pathogenic.

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

From GeneDx, SCV000490962.2

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

Description

Reported previously in association with a milder, later-onset ornithine transcarbamylase (OTC) deficiency phenotype in males as well as a late-onset, mild phenotype in heterozygous females (Pinner et al. 2010; Cavicchi et al. 2014); Reported to be associated with 26-35% residual OTC enzyme activity when expressed in CHO cells (Augustin et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9175746, 17334707, 32995020, 32934962, 9048915, 25026867, 7951259, 11768581, 11260212, 8863155, 30449781, 28324312, 31447099, 11102556, 21070677, 33272297)

#	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 Eurofins Ntd Llc (ga), SCV000854966.1

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

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV004026360.1

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

Description

PS4, PP3, PM2_SUP

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV004226706.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (12)

Description

PP1, PP4, PM2, PM5, PS3

#	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		1	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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