ClinVar

Description

The m.5631G>A in MT-TA has been reported in one individual to date, in a woman with adult-onset myopathy (PMID: 25873012). Her muscle biopsy showed numerous COX-deficient fibers and ragged red fibers. Decreased activities of mitochondrial respiratory chain enzymes complexes I, II/III, and IV were noted although values were not provided. The variant was present in the proband at 92% in muscle, 77% in blood, 77% in hair shafts, 69% in urinary epithelial cells, and 44% in buccal sample. As this is the only case reported to date, PS4 could not be applied. Her healthy mother had the variant present at lower heteroplasmy levels (8% blood, 4% urine, 6% buccal sample) however, given no additional family members were tested, segregation evidence (PP1) could not be applied. There are no reported de novo occurrences of this variant to our knowledge. Computational predictors are conflicting precluding consideration of PP3 or BP4 (MitoTIP: 43.4%; HmtVAR: 0.45). There is one occurrence of this variant in Mitomap's 61, 134 sequences (AF=0.002%; Hg L0a); one heteroplasmic occurrence in Helix's 195,983 sequences (AF=0.001%; 10-20% heteroplasmy, Hg W); and one heteroplasmic occurrence in gnomAD v3.1.2 (0.002%; Hg V, PM2_supporting). Single fiber testing showed higher levels of the variant in COX deficient fibers (n=18; 95.1% +/- 0.45) than in COX positive fibers (n=22; 83.8% +/- 3.38; PS3_supporting, PMID: 25873012). 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 February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting.