The NM_000531.6:c.617T>G variant in OTC is a missense variant predicted to cause substitution of methionine by arginine at amino acid 206 (p.Met206Arg). One male patient with this variant displayed in the first few days of life hyperammonemia, high glutamine, high orotic acid, and reduced liver OTC activity, which is highly specific for OTC deficiency (PP4_Moderate, PMID: 10405441). The variant was not detected in the unaffected mother of this patient by targeted testing (PM6). This variant has been reported in 1 additional proband with biochemical and clinical evidence of OTC deficiency (PS4_Supporting; PMID: 25994866). This variant is absent from gnomAD v4.1 (PM2_Supporting). Growth assay in yeast showed <50% of wild-type OTC growth activity, indicating that this variant impacts protein function (PMID: 37146589, PS3_Moderate). The computational predictor REVEL gives a score of 0.875, which is between 0.773 and 0.932, evidence that correlates with moderate impact to OTC function (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for X-linked ornithine carbamoyltransferase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Urea Cycle Disorders VCEP (OTC specifications version 1.0.0), 02/10/2025: PP4_Moderate, PM6, PS4_Supporting, PM2_Supporting, PS3_Moderate, PP3_Moderate.