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.
|
