The NM_000531.6:c.1052del (p.K351Sfs*44) variant in OTC is a frameshift variant predicted to cause a shift of the reading frame of the protein and extension beyond the Ter354 and a novel Ter395 within the last exon of the gene. While this variant is expected to escape nonsense mediated decay it is predicted to alter a region that is critical to protein function (amino acids 345-354) and per ClinGen UCD VCEP specifications, alteration including these regions is applicable at a weight of Strong (PVS1_Strong). This variant has been detected in at least 1 individual with OTC deficiency (PMID: 34014569, PMID: 34014557, ClinVar SCV001281637.1) (PS4_Supporting). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in one individual with OTC deficiency (ClinVar SCV001281637.1) (PM6_Supporting). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic 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): PVS1_Strong, PS4_Supporting, PM2_Supporting, PM6_Supporting.