ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.809A>G (p.Gln270Arg) (rs1800328)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000117884 SCV000296930 benign not specified 2015-11-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000117884 SCV000304706 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000715832 SCV000846663 benign History of neurodevelopmental disorder 2014-12-13 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
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
Integrated Genetics/Laboratory Corporation of America 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.
Genetic Services Laboratory,University of Chicago RCV000117884 SCV000152157 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.
SingHealth Duke-NUS Institute of Precision Medicine RCV000335039 SCV000853172 uncertain significance Ornithine carbamoyltransferase deficiency 2017-06-07 no assertion criteria provided curation

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