ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 28324312, 30612563, 29961769)

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.

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.

The p.Gln270Arg variant in OTC is classified as benign because it has been identified in 4.37% (4039/92426) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.

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.