ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.137A>G (p.Lys46Arg) (rs1800321)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079082 SCV000110951 benign not specified 2018-05-30 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000079082 SCV000304699 benign not specified 2016-02-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2018-08-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000715362 SCV000846191 benign History of neurodevelopmental disorder 2014-11-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
OMIM RCV000011741 SCV000031973 benign ORNITHINE TRANSCARBAMYLASE POLYMORPHISM 1988-02-01 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.

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