Mitochondrial Diseases VCEP
The m.8306T>C variant in MT-TK has been reported in three individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 22925535, 23847141, 34354612). The first case was reported in 2012 and was a man with onset at 30 years with progressive concerns over time. His medical concerns included muscle weakness, muscle atrophy, cardiac arrhythmia, dysphagia, hearing loss, and insulin resistance. Muscle biopsy showed ragged red fibers and COX-negative fibers, and muscle CT showed bilateral atrophy with fatty replacement. The variant was present at 98% in muscle, 30% in hair roots, 27% in urine, 17% in buccal, and 5% in blood (PMID: 22925535). The other two cases were part of cohort reports with limited clinical details provided (PMIDs: 23847141, 34354612). This variant was reported in additional individuals in one publication (PMID: 29663531) however these cases were excluded from this curation as it was unclear which case(s) had this variant. Furthermore, several cases in this series came from consanguineous families and other nuclear genetic etiologies were not excluded (PMID: 29663531). There are no large families reported in the medical literature to consider for evidence of segregation. While this variant was absent in blood, buccal, hair, and urine from healthy siblings of one proband, the mother was not available for testing to confirm a de novo occurrence (PMID: 22925535). The computational predictor MitoTIP suggests this variant is pathogenic (88.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.7 (PP3). This variant is absent in the Genbank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (97.4% +/- 1.2, n=11) than in COX-positive fibers (18.8% +/- 9.2, n+10), p<0.0001 (PS3_supporting, PMID: 22925535). 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 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PS3_supporting.
