Table 2.

The pathogenicity scoring system. The table reports the update of the pathogenicity scoring system according to Yarham criteria (Yarham et al., 2011) and further improved in HmtVar (Preste et al., 2019)

The pathogenicity scoring criteria		Score
Variant described as pathogenic by more than one report	yes	2
	no	0
PhastCons conservation	yes	1
	no	0
PhyloP conservation	yes	1
	no	0
Heteroplasmy evidences	yes	2
	no	0
Segregation of mutation with disease	yes	2
	no	0
Histochemical evidence of mitochondrial disease	yes	2
	no	0
Biochemical defect in OXPHOS complexes I, III, IV	yes	2
	no	0
Pathogenicity evidence in trans‐mitochondrial cybrids or mutant mt‐tRNA steady‐state level studies	yes	5
	no	0
Evidence of mutation segregation with biochemical defect from single‐fiber studies	yes	3
	no	0

Each of the criteria is associated with a weighted score allowing classification of human mitochondrial tRNA variant pathogenicity. The improvements applied in Preste et al., (2019) is focused on PhyloP and PhastCons usage to evaluate the inter‐mammalian site conservation.