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

dbSNP: rs72554308

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000011761	SCV000485682	pathogenic	Ornithine carbamoyltransferase deficiency	2016-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000083333	SCV000490962	pathogenic	not provided	2021-04-06	criteria provided, single submitter	clinical testing	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)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000011761	SCV000840025	pathogenic	Ornithine carbamoyltransferase deficiency	2017-05-25	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000083333	SCV000854966	pathogenic	not provided	2017-12-07	criteria provided, single submitter	clinical testing
Invitae	RCV000011761	SCV000945273	pathogenic	Ornithine carbamoyltransferase deficiency	2024-01-25	criteria provided, single submitter	clinical testing	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.
Genome-Nilou Lab	RCV000011761	SCV002033213	pathogenic	Ornithine carbamoyltransferase deficiency	2021-11-07	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000083333	SCV004026360	likely pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	PS4, PP3, PM2_SUP
Baylor Genetics	RCV000011761	SCV004040714	pathogenic	Ornithine carbamoyltransferase deficiency	2023-01-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000083333	SCV004226706	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	PP1, PP4, PM2, PM5, PS3
OMIM	RCV000011761	SCV000031993	pathogenic	Ornithine carbamoyltransferase deficiency	2001-11-01	no assertion criteria provided	literature only
GenMed Metabolism Lab	RCV000083333	SCV000115419	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Natera, Inc.	RCV000011761	SCV002087161	pathogenic	Ornithine carbamoyltransferase deficiency	2021-05-10	no assertion criteria provided	clinical testing