The disease score is a value ranging from 0 to 1, useful to discriminate benign from pathogenic mitochondrial variants.

Disease scores for non-synonymous variants are calculated based on the algorithm implemented in Santorsola et al, derived from the weighted mean of the following six pathogenicity predictors:

Disease scores for tRNA variants are calculated based on criteria reported in Diroma et al, derived from Yarham et al but normalized into the range 0-1. At present, disease scores are available for any observed and potential tRNA variant, according to the criteria detailed below.

tRNA Scoring Criteria Yes No
tRNA structure parameters and reports
Variant described as pathogenic by more than one report 2 0
Frequency and population data
PhastCons conservation 1 0
PhyloP conservation 1 0
Variant Heteroplasmy
Heteroplasmy evidences 2 0
Evidences from functional studies
Segregation of mutation with disease 2 0
Histochemical evidence of mitochondrial disease 2 0
Biochemical defect in OXPHOS complexes I, III or IV 2 0
Pathogenicity evidence in trans mitochondrial cybrids or mutant mt-tRNA steady state level studies 5 0
Evidence of mutation segregation with biochemical defect from single-fiber studies 3 0

Disease Score Thresholds

Disease Scores represent a tool to discriminate benign from pathogenic variants; to this aim specific Disease Score Thresholds (DST) were defined. For non-synonymous variants, the DST was fixed to 0.43 according to Santorsola et al, while for tRNA variants it was fixed to 0.35 according to Diroma et al. However, in order to reinforce variants pathogenicity assignments, both the protocols associated DST values to nucleotide variability thresholds (nt_var_T), as further described in the nucleotide variability page.

Instead of nucleotide variability we use the Allele Frequency (AF) value and the related Allele Frequency Threshold (AFT), which allow for a more reliable pathogenicity assignment.

Tiers definition

In order to assign each non-synonymous or tRNA variant to a specific pathogenicity tier, DST and AFT were considered, according to the general rules shown below.

Tier Disease Score range Allele Frequency range
Polymorphic DS < DST AF > AFT
Likely Polymorphic DS < DST AF ≤ AFT
Likely Pathogenic DS ≥ DST AF > AFT
Pathogenic DS ≥ DST AF ≤ AFT

According to the specific thresholds defined above, the final pathogenicity tiers were defined as reported in the pathogenicity page.