The m.15990C>T variant in MT-TP gene has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). The age of onset ranged from the first decade of life to adulthood. Features seen in these individuals include chronic progressive external ophthalmoplegia (CPEO), myopathy, and exercise intolerance (PMIDs: 32305257, 7689388, 8190311). The variant occurred de novo in both individuals (PM6; PMIDs: 7689388, 8190311, 32305257). There are no other large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (51.7 percentile) but HmtVAR predicts it to be neutral with a score of 0.1. Single fiber testing in both reported individuals support the functional impact of this variant (PS3_supporting). In one study, there were higher levels of the variant in COX-negative fibers (91-97%) than in COX-positive fibers (63-86%, p= < 0.001; PMID: 7689388). In the other study, there were again higher levels of the variant in COX-negative fibers (89.75 ± 6.84%, n = 20) than in COX-positive fibers (14.00 ± 6.84 %, n = 17; p < 0.001; PMID: 32305257). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent phenotype and functional testing performed in each reported individual. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PM6, PS3_supporting.