The NM_000531.6:c.275G>A (p.Arg92Gln) variant in OTC is a missense variant in biologically relevant exon 3. Computational evidence strongly suggests that this variant affects protein function (PP3_Strong). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in the literature in 7 patients; 3 described as having OTC deficiency, but no details were provided regarding plasma amino acids/ammonia, urine orotic acid, or enzyme activity in patient cells; 1 patient was a male with neonatal onset disease (PMID: 1671317); disease onset and sex information were not provided for 2 patients (PMID: 19138872). Clinical and biochemical symptoms were described for the remaining 4 patients (PMID: 26753873, 10799432, 36303552, 34670952) (PS4). Biochemical symptoms, specific to OTC deficiency, were reported in the literature for 2 patients (PMID: 30285816, 33272297; PP4_Moderate). This variant is located in a critical and well-established functional domain (the carbamylphosphate binding site at Arg-92) [PMID:9852088, 10813810, 11237854] (PM1). Additionally, this variant has been shown to result in <5% wild-type OTC growth activity in yeast assay, suggesting that this variant may impact protein function (PMID: 37146589, PS3_Supporting). In summary, this variant meets the criteria to be classified as a pathogenic variant for OTC deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Urea Cycle Disorders Variant Curation Expert Panel (OTC specifications version 1.0.0): PP3_Strong, PM2_Supporting, PS4, PP4_Moderate, PM1, PS3_Supporting