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

dbSNP: rs68031618

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	2023-08-19	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 10993). This missense change has been observed in individual(s) with OTC deficiency (PMID: 2474822, 25994866). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 26 of the OTC protein (p.Arg26Gln). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon.
Genome-Nilou Lab	RCV000011740	SCV002033211	pathogenic	Ornithine carbamoyltransferase deficiency	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408456	SCV002673302	likely pathogenic	Inborn genetic diseases	2016-06-10	criteria provided, single submitter	clinical testing	The c.77G>A variant (also known as p.R26Q), located in coding exon 1 of the OTC gene, results from a G to A substitution at nucleotide position 77. This change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the arginine at codon 26 to glutamine, an amino acid with highly similar properties. This variant was identified in a hemizygous state in a Hispanic male patient with neonatal clinical OTC deficiency. Analysis of a liver biopsy from this patient revealed lack of mRNA and enzyme activity (Grompe M et al. Proc. Natl. Acad. Sci. U.S.A. 1989 Aug;86(15):5888-92). This variant was previously reported in the SNPDatabase as rs68031618. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples with coverage at this position. Both the nucleotide and amino acid positions are not well conserved in available vertebrate species. Using the ESEfinder splice site prediction tool, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct experimental evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
OMIM	RCV000011740	SCV000031972	pathogenic	Ornithine carbamoyltransferase deficiency	1989-08-01	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.