The m.7497G>A variant in MT-TS1 has been reported in three unrelated individuals with primary mitochondrial disease with shared features of exercise intolerance, proximal myopathy, lactic acidosis, and myalgia. Age at presentation ranged from three years old to the 30s. Muscle biopsies showed ragged red fibers, COX-negative fibers, and reduced activities of complexes I and IV. All probands were homoplasmic for the variant in muscle and it was present in various other tissues at levels >90%. (PS4_supporting; PMIDs: 14605505, 9778262). This variant segregated with disease in each of the three families reported (PP1_moderate). The probands were homoplasmic for the variant muscle and/or blood. In one family, the unaffected mother harbored the variant at 10% in blood (PMID: 14605505). In the second family, the unaffected mother harbored the variant at 62% and the unaffected brother had the variant at 62% in blood (PMID: 9778262). In the third family, an affected daughter with myalgia had the variant at 90% in blood and an unaffected brother has the variant at 70% (PMID: 9778262). There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (92.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activities (PS3_supporting, PMID: 16199753). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PS3_supporting, PM2_supporting, PP3.