ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.76C>T (p.Arg26Trp) (rs1057515879)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000363211 SCV000482289 uncertain significance Ornithine carbamoyltransferase deficiency 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589394 SCV000697262 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing Variant summary: The OTC c.76C>T (p.Arg26Trp) variant involves the alteration of a non-conserved nucleotide. This variant is located within the carbamoyl-P binding domain. 3/5 in silico tools predict a benign outcome for this variant, however this particular alteration has yet to be functionally assessed. . This variant is absent from control population dataset of ExAC. The variant was identified in a pt undergoing WES due to clinical presentations nonspecific and unrelated to ornithine transcabamylase deficiency, although, pt did report episodes of memory loss. The variant was inherited from reportedly unaffected father. Another alteration of the same codon, p.R26Q has been reported in several affected individuals with biochemically confirmed OTC-deficiency. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, but was cited as VUS by a reputable database/clinical diagnostic laboratory. The p.R26W may represent either a late-onset mild mutation or rare functional variant. At this point, there is no sufficient evidence to classify c.76C>T with confidence. Taken together, this variant is classified as VUS.
Invitae RCV000363211 SCV000756192 uncertain significance Ornithine carbamoyltransferase deficiency 2018-01-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 26 of the OTC protein (p.Arg26Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with OTC-related disease. ClinVar contains an entry for this variant (Variation ID: 368257). 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 tryptophan 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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