OTC p.Arg40His

The c.119G>A variant in OTC is a missense variant predicted to cause substitution of arginine by histidine at amino acid 40 (p.Arg40His). One patient with this variant displayed hyperammonemia, elevated glutamine, normal citrulline, with elevated urine orotic acid, which is highly specific for ornithine transcarbamylase deficiency (PMID:25026867; PP4_Moderate). This variant has been reported in 13 additional male and 1 female probands with biochemical or clinical evidence of OTC deficiency (PMID:6635166, 9286441, 23209112, 17334707, 7860066, 19893582, 25026867, 21070677, 11260212, 9048915; PS4_VeryStrong). 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 have a impact protein function (PMID: 37146589; PS3_Supporting). Multiple affected family members (≥5 informative segregations, PP1 strong; PMID:16635166, 9286441, 11260212, 9048915). Another missense variant c.118C>T (p.Arg40Cys) is Pathogenic/Likely Pathogenic, and c.119G>T (p.Arg40Leu) is Likely Pathogenic in ClinVar, however PM5 criteria is not being utilized in this curation. The computational predictor REVEL gives a SCORE of 0.613, which is below the threshold of 0.644, evidence that correlates with uncertain impact to OTC function. 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: PP4_Moderate (+2), PS4_VeryStrong (+8), PM2_Supporting (+1), PS3_Supporting (+1), PP1_Strong (+4)