The m.4291T>C variant in MT-TI has been reported in five probands with primary mitochondrial disease (PMIDs: 15498972, 34607911; PS4_moderate). Affected individuals had variable hypomagnesemia and hypokalemia (consistent with Gitelman-like syndrome), migraines, sensorineural hearing loss, and hypertrophic cardiomyopathy. In one affected individual, ragged red fibers, increased subsarcolemmal staining, cytoplasmic lipid accumulation, increased glycogen, and dysmorphic cristae were seen on muscle biopsy (PMID: 15498972). The variant was present at homoplasmy or near homoplasmy in all reported individuals. While the variant was also present at high levels in unaffected family members, no children of affected fathers had clinical features in one large pedigree (PMID: 15498972, PP1). Fibroblasts from affected individuals showed decreased maximal mitochondrial respiration and reduced complex IV activity (PMID: 34607911; PP4). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is possibly benign (31.8 percentile) but HmtVAR predicts it to be deleterious with a score of 0.4. There are no cybrids or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. Of note, this is a highly compelling variant of uncertain significance given the consistent phenotype in affected individuals. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PP4, PM2_supporting.