Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing
Table 2
Classification of variants into five pathogenicity classes.
Pathogenicity class
Conclusion
Criteria
5
certainly pathogenic
(1) Reported pathogenic in at least two unrelated cases (2) and/or functional studies reveal effect on protein structure/function (3) and zygosity/inheritance of phenotype fits the variant (4) and phenotype-genotype correlation with previously published literature
4
likely pathogenic
(1) Reported pathogenic in one case (2) and/or predicted pathogenic in at least 2 of 4 variant prediction tools: SIFT [28], Polyphen [29], Align GVGD [30], and Mutation Taster [31] through the Alamut interface (3) and/or predicted loss or gain of splice site predicted in at least 4 of 5 splice site predictors: SpliceSiteFinder [32], MaxEntScan [33], NNSPLICE [34], GeneSplicer [35], and Human Splicing Finder [36] through the Alamut interface (4) and/or close proximity to known pathogenic mutations with similar or lower variant prediction score (5) and zygosity/inheritance of phenotype fits the variant (6) and phenotype-genotype correlation with previously published literature
3
uncertain pathogenic
(1) Present in ≤0.1% of dbSNP135 or 1000 genomes (2) and/or present in ≤1 in-house control (3) and zygosity/inheritance of phenotype in family fits the variant (4) Variants in class 2 may be lifted to this class if present in several affected patients with similar phenotype
2
unlikely pathogenic
(1) Present in 0.1–1% of dbSNP135 or 1000 genomes (2) and/or present in 2-3 in-house controls (3) and/or predicted no loss or gain of splice site predicted by 5/5 splice site predictors (applies only to synonymous variants and variants in introns and UTRs) (4) and/or reported benign in the literature
1
certainly not pathogenic
(1) Present in ≥1% of dbSNP135 or 1000 genomes (2) and/or present in ≥4 in-house controls
dbSNP = the single nucleotide polymorphism database.