Submissions for variant NM_000531.6(OTC):c.809A>G (p.Gln270Arg)

gnomAD frequency: 0.02868  dbSNP: rs1800328

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000117884	SCV000152157	benign	not specified	2022-01-19	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000117884	SCV000296930	benign	not specified	2015-11-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000117884	SCV000304706	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000335039	SCV000482297	benign	Ornithine carbamoyltransferase deficiency	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000335039	SCV000631862	benign	Ornithine carbamoyltransferase deficiency	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312203	SCV000846663	benign	Inborn genetic diseases	2014-12-13	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000335039	SCV000884270	benign	Ornithine carbamoyltransferase deficiency	2018-08-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000335039	SCV001141828	benign	Ornithine carbamoyltransferase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000117884	SCV001364020	benign	not specified	2019-03-14	criteria provided, single submitter	clinical testing	Variant summary: OTC c.809A>G (p.Gln270Arg) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.029 in 200020 control chromosomes, predominantly at a frequency of 0.043 within the Non-Finnish European subpopulation (including 50 homozygotes) and at a frequency of 0.035 within Finnish European subpopulation (6 homozygotes) in the gnomAD database. The observed variant frequency within Non-Finnish/Finnish European control individuals in the gnomAD database is approximately 9 and 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTC causing Ornithine Transcarbamylase Deficiency phenotype (0.0046) respectively, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish/Finnish European origin. The variant c.809A>G has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency without strong evidence of causality (Reish_1993, Dobrowolski_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (X4 Benign/likely benign and 1X uncertain significance). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000335039	SCV001737162	benign	Ornithine carbamoyltransferase deficiency	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001705850	SCV001859311	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28324312, 30612563, 29961769)
Fulgent Genetics, Fulgent Genetics	RCV000335039	SCV002804192	benign	Ornithine carbamoyltransferase deficiency	2022-04-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000335039	SCV004357054	benign	Ornithine carbamoyltransferase deficiency	2018-03-05	criteria provided, single submitter	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV000335039	SCV000853172	uncertain significance	Ornithine carbamoyltransferase deficiency	2017-06-07	no assertion criteria provided	curation
Natera, Inc.	RCV000335039	SCV002087182	likely benign	Ornithine carbamoyltransferase deficiency	2019-11-26	no assertion criteria provided	clinical testing