Submissions for variant NM_000531.6(OTC):c.137A>G (p.Lys46Arg)

gnomAD frequency: 0.26575  dbSNP: rs1800321

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079082	SCV000110951	benign	not specified	2018-05-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079082	SCV000304699	benign	not specified	2016-02-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000268490	SCV000482290	benign	Ornithine carbamoyltransferase deficiency	2018-01-13	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000268490	SCV000604577	benign	Ornithine carbamoyltransferase deficiency	2021-10-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311511	SCV000846191	benign	Inborn genetic diseases	2014-11-24	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000079082	SCV001364019	benign	not specified	2019-03-14	criteria provided, single submitter	clinical testing	Variant summary: OTC c.137A>G (p.Lys46Arg) results in a conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain (IPR006132) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.19 in 199288 control chromosomes, at a frequency of 0.23 within the Non-Finnish European subpopulation (including 1588 homozygotes) and at a frequency of 0.39 within African subpopulation (including 943 homozygotes) in the gnomAD database,. The observed variant frequency within Non-Finnish European/African control individuals in the gnomAD database is approximately 50 and 85 fold respectively of the estimated maximal expected allele frequency for a pathogenic variant in OTC causing Ornithine Transcarbamylase Deficiency phenotype (0.0046), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European/African origin. The variant, c.137A>G has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency without strong evidence of causality (Engel_2008, Zhong_2013, Dobrowolski_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000268490	SCV001717686	benign	Ornithine carbamoyltransferase deficiency	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001725114	SCV001960466	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30612563, 28324312)
Color Diagnostics, LLC DBA Color Health	RCV000268490	SCV004357045	benign	Ornithine carbamoyltransferase deficiency	2018-03-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001725114	SCV005276120	benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000011741	SCV000031973	benign	ORNITHINE TRANSCARBAMYLASE POLYMORPHISM	1989-08-01	no assertion criteria provided	literature only
Genetic Services Laboratory, University of Chicago	RCV000079082	SCV000152156	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Natera, Inc.	RCV000268490	SCV001458516	benign	Ornithine carbamoyltransferase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000079082	SCV001919152	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079082	SCV001958423	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079082	SCV001969520	benign	not specified		no assertion criteria provided	clinical testing