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.