The NM_000531.6:c.817_819del variant in OTC is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid (p.Glu273del) in a non-repeat region (PM4). One male patient with this variant developed at 10 months of age hyperammonemic coma, and OTC enzymatic activity in liver tissue was reduced (5% wildtype) which is highly specific for OTC deficiency (PP4_Moderate, PMID 8956045). This variant has been reported in 4 additional probands (3 male, 1 female) with biochemical and clinical evidence of OTC deficiency, with onset between 1.5 months and 18 years (PS4_Moderate; PMID: 34014557, 10799432, 17334707, 32420033). This variant has been reported not to segregate with clinical phenotype in two affected individuals from separate families, including a 64-year-old uncle of one proband and the older brother of another (BS4_Supporting; PMID 34014557, 32420033). The group max filtering allele frequency (Grpmax FAF) in gnomAD v4.1 is 3.800e-7 in European (non-Finnish) population, with 1 hemizygotes across all populations. This is lower than the ClinGen UCD VCEP threshold (<1.5e-5 AND ≤1 hemizygotes) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked ornithine carbamoyltransferase deficiency. Although there are both pathogenic and benign types of evidence, this variant is associated with late-onset OTC deficiency, expression and penetrance may vary depending on environmental factors, and the absence of clinical phenotype in the individuals reported above is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Urea Cycle Disorders VCEP (OTC specifications version 1.0.0), 02/09/2025: PM4, PP4_Moderate, PS4_Moderate, PM2_Supporting, BS4_Supporting.