The relationship between OTC and ornithine carbamoyltransferase deficiency (X-linked) was evaluated using the ClinGen Clinical Validity Framework as of February, 2019. The OTC gene is located on the X chromosome and encodes a mitochondrial matrix enzyme that catalyzes the second step of the urea cycle. Most patients with OTC deficiency are hemizygous males, but female carriers can also be symptomatic. Variants in OTC were first reported in humans with this disease as early as 1985 (Rozen et al., PMID 2983225). More than 400 variants (missense, nonsense, frameshift, in-frame indels, and large deletions) have been reported in humans (Caldovic et al., 2015, PMID 26059767). Evidence supporting this gene-disease relationship includes case-level and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by biochemical assays, expression studies, and model systems. In summary, OTC is definitively associated with X-linked ornithine carbamoyltransferase deficiency . This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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