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Criteria for Assessment of Variant Pathogenicity

For Mitomap to assign a status of "Cfrm" to a possibly pathogenic variant, we look for confirming reports which address the criteria outlined in Mitchell et al 2006, Yarham et al 2011, Wong 2007, and Gonzalez-Viogue et al 2014. The following table shows the points we take into consideration. A new scoring system is under development and will be linked here once published.

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.
Topic revision: r2 - 18 Sep 2019, MarieLott

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