Criteria for Assessment of Variant Pathogenicity

MITOMAP Variant Assessment: Pathogenicity Criteria

• Independent reports of two or more unrelated families with evidence of similar disease
• Evolutionary conservation of the nucleotide (for RNA variants) or amino acid (for coding variants)
• Presence of heteroplasmy
• Correlation of variant with phenotype / segregation of the mutation with the disease related to the mutant load within a family
• Biochemical defects in complexes I, III, IV, or V of the respiratory chain in affected or multiple tissues
• Functional studies showing differential defects segregating with the mutation (cybrid or single fiber studies)
• Histochemical evidence of a mitochondrial disorder
• For fatal or severe clinical phenotypes, the absence or extremely rare occurrence of the variant in large mtDNA sequence databases.