Rationale: OTC deficiency, an X-linked recessive condition caused by pathogenic variants in the OTC gene, can range from severe neonatal disease to a later onset, milder phenotype, with possible developmental delays, variable degree of cognitive impairment, seizures, and other neurological problems. The gene is included on many epilepsy panels and expanded carrier screening. A positive test result has implications not only for the patient’s clinical management, but also for reproductive risk assessment. This case study details a patient with a likely pathogenic variant in the gene, but with no evidence of the disease, which highlights the importance of understanding the limitations of variant classification for accurate diagnoses and reproductive risk counseling. Methods: A 9-year old boy with febrile seizures underwent an epilepsy gene panel which identified a likely pathogenic variant in OTC c.385C >T (p.Arg129Cys). Ammonia, serum amino acids, and purines and pyrimidines panel were performed as follow up. Additionally, Sanger sequencing of the gene with another lab was performed. Results: The first lab classified the OTC variant as likely pathogenic based on the following ACMG criteria: PM1 (located in a mutational hot spot and or critical and well established functional domain), PM2 (absent from controls (or at extremely low frequency if recessive), PM5 (novel missense change at amino acid residue where a different missense change determined to be pathogenic has been seen before), PP3 (multiple lines of computational evidence support a deleterious effect on the gene or gene product). Additionally, the variant had been reported in a patient with clinical OTC deficiency. Our patient’s ammonia, serum amino acids, and purines and pyrimidines were all essentially normal. Sanger sequencing with a different lab confirmed the presence of the variant, but classified it as a variant of uncertain significance due to lack of conclusive functional evidence. In light of normal biochemical testing and conflicting variant interpretation, the patient was determined unlikely to have OTC deficiency. Conclusions: We report an OTC variant that meets numerous ACMG criteria for pathogenicity; however, the patient does not have the gene’s associated disease. In the setting of a positive genetic test result, understanding the limitations of variant classification is critical to providing accurate diagnoses and reproductive risk counseling. Additionally, report of this specific variant is important because it provides important clinical evidence in contrast to a previous publication that can be used for more accurate variant interpretation and reproductive risk counseling. Funding: Please list any funding that was received in support of this abstract.: Not applicable
