The m.3290T > C variant might be a protective factor against the pathogenic m.3243 A > G variant: a case study.

The mitochondrial m.3243 A > G variant is a prevalent mitochondrial disease mutation that causes multisystem maternal inheritance disorders. While clinical severity typically correlates with mutation load, symptom manifestation may be influenced by other variants and environmental factors. Notably, the m.3290T > C variant has been hypothesized as a potential protective variant for m.3243 A > G pathogenicity, though clinical evidence remains limited. Here we reported a six-generation Chinese pedigree carrying both m.3243 A > G and homoplasmic m.3290T > C variants. Clinical and genetic analyses revealed that carriers with extremely high m.3243 A > G heteroplasmy (> 95%) exhibited severe symptoms, whereas those with moderate or high levels showed limited or no clinical symptoms. Our findings provide novel evidence for the protective role of m.3290T > C in mitigating m.3243 A > G pathogenicity, highlighting its potential clinical significance.