ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.77G>A (p.Arg26Gln) (rs68031618)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000011740 SCV000917917 pathogenic Ornithine carbamoyltransferase deficiency 2018-02-08 criteria provided, single submitter clinical testing Variant summary: OTC c.77G>A (p.Arg26Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 86719 control chromosomes in ExAC and the literature. The c.77G>A variant has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (Grompe_1989, Kim_2006, Kim_2015, Arranz_2007, Shao_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000011740 SCV001220838 pathogenic Ornithine carbamoyltransferase deficiency 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 26 of the OTC protein (p.Arg26Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 1 of the OTC coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs68031618, ExAC 0.002%). This variant has been observed in several individuals affected with OTC deficiency (PMID: 2474822, 25994866, ). ClinVar contains an entry for this variant (Variation ID: 10993). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098, 23769969). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000011740 SCV000031972 pathogenic Ornithine carbamoyltransferase deficiency 2017-01-26 no assertion criteria provided literature only
GenMed Metabolism Lab RCV000083565 SCV000115651 pathogenic not provided no assertion criteria provided not provided Converted during submission to Pathogenic.

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