The NM_000531.6(OTC):c.118C>T variant in OTC is a missense variant predicted to cause substitution of Arg by Cys at amino acid 40 (p.Arg40Cys). Predictor REVEL gives a score of 0.902, which is between 0.773 and 0.932, and Moderate evidence of impact on OTC function (PP3_Moderate). The p.Arg40Cys also has one patient with this variant displaying hyperammonemia, urinary orotate, 3% OTC activity, which is highly specific for OTC deficiency (PMID: 7860066; PP4_Moderate). Another missense variant [c.119G>A, p.Arg40His; ClinVar Variation ID 11014], in the same codon, has been classified as pathogenic for OTC deficiency by the ClinGen Urea Cycle Disorders VCEP (PM5). The growth assay in yeast showed 31.1±0.07% of wild-type OTC growth activity, indicating that this variant impacts protein function (PMID: 37146589, PS3_Moderate). The Grpmax Filtered allele frequency in gnomAD v4.1.0 is 0.00000917, which is lower than the ClinGen UCD VCEP’s threshold for PM2_Supporting (<0.000015), however, there are 6 hemizygotes across all populations. While the presence of 6 hemizygotes meets BS2 criterion as specified by the UCD VCEP, this variant is excluded from BS2 given its known late onset phenotype. This variant has been reported in 1 additional proband with hyperammonemia and orotic aciduria (PMID: 20406775; PS4_supporting). The variant has been reported to segregate with OTC in the mother and sister affected PP1_SUPPORTING; PMID:7860066 In summary, this variant meets the criteria for being classified as likely pathogenic for OTC deficiency. ACMG/AMP criteria applied, as specified by the ClinGen UCD VCEP (OTC specifications version 1.0.0): PP3_moderate (+2), PP4_Moderate (+2), PM5 (+2), PS3_Moderate (+2), and PS4_Supporting (+1).