The relationship between OAT and gyrate atrophy of the choroid and retina, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 2, 2019. OAT encodes ornithine aminotransferase, a mitochondrial enzyme that catalyzes the pyridoxal 5′-phosphate-dependent transformation of L-ornithine to L-glutamate 5-semialdehyde, which spontaneously forms pyrroline-5-carboxylate. Variants in OAT causing gyrate atrophy were first reported in 1988 (Ramesh et al, PMID 3375240; Mitchel et al, PMID 3339136). Hyperornithininemia is a consistent biochemical finding in these patients. Data from 10 patients with 13 unique variants (missense, nonsense, frameshift, splicing, large deletion) from 6 publications were curated (Mitchel et al, 1988, PMID 3339136; Ramesh et al, 1988, PMID 3375240; Mitchel et al, 1989, PMID 2492100; Mashima et al, 1992, PMID 1609808; Doimo et al, 2013, PMID 23076989; Katagiri et al, 2014, PMID 24429551). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. Of note, rare individuals with OAT deficiency have been reported who presented with hyperammonemia and low ornithine in the neonatal period, later developing hyperornithinemia (Cleary et al, 2005, PMID 16151897; Zubarioglu et al, 2016; PMID 27037922). While these individuals had no signs of gyrate atrophy, it is possible that it may develop later in life. The relationship between OAT and gyrate atrophy is supported by extensive experimental evidence including the biochemical function of ornithine aminotransferase, which is consistent with the biochemical features of the disease (Juncosa et al, 2103, PMID 23747282), expression of OAT in the retina (Bernstein et al, 1988, PMID 9815288), functional studies in patient and non-patient cells (Heinänen et al, 1988, PMID 9727717; Montioli et al, 2018, PMID 30251682), as well as the phenotype in naturally-occurring and knock-out mouse models (Bisaillon et al, 2014, PMID 25264521; Wang et al, 1995, PMID 7550347; Wang et al, 2000, PMID 10655512). In summary, OAT is definitively associated with gyrate atrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.
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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