ClinVar

Description

The m.4308G>A variant in MT-TI has been reported in two unrelated individuals with primary mitochondrial disease with onset ranging from the first decade to third decade of life and features include bilateral ptosis, chronic progressive external ophthalmoplegia (CPEO), exercise intolerance, decreased BMI, and hyperCKemia. Muscle biopsy showed paracrystalline inclusions, ragged red fibers, COX negative fibers, and respiratory chain deficiencies across complexes I, III, and IV. In both cases, the variant was undetectable in blood when the individuals were tested in their 30s and 50s. The variant was heteroplasmic in muscle, however the exact heteroplasmy level was only reported in one of these cases at 47%. Neither case had any positive family history (PS4_supporting; PMIDs: 20884012; 21292040). This variant occurred de novo in one individual (absent in blood and muscle from mother via RFLP; PM6_supporting, PMID: 21292040). There are no 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). The computational predictor MitoTIP suggests this variant is pathogenic (82.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). There are no cybrids, single fiber studies, or other functional assays 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. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PM2_supporting, PP3, PM6_supporting.