. Author manuscript; available in PMC: 2014 Aug 1.

Published in final edited form as: Circ Cardiovasc Genet. 2013 Jul 16;6(4):10.1161/CIRCGENETICS.113.000039. doi: 10.1161/CIRCGENETICS.113.000039

Table 1.

Criteria for gene variant assignment of pathogenicity class 1 to 5

Designation	Novel	Novel	Pathogenic	Pathogenic	VUS	Benign
Mutation Type	Missense In-frame insertion/deletion	Nonsense Frameshift Splice	Missense In-frame insertion/deletion	Nonsense Frameshift Splice	Any	Any
Class 5 (Pathogenic)		ClinSeq^®/ESP MAF ≤ disease prevalence AND sufficient race-matched control data AND
Class 5 (Pathogenic)		Multiple LOF reported as pathogenic, consistent FHx	≥ 3 reported cases as pathogenic and no evidence against or 2 cases with supporting evidence	Multiple LOF reported as pathogenic and no evidence against
Class 4 (Likely pathogenic)		ClinSeq^®/ESP MAF ≤ disease prevalence AND
Class 4 (Likely pathogenic)		Multiple LOF mutations reported as pathogenic, equivocal FHx	Single reported case as pathogenic with supporting evidence OR 2 reported cases as pathogenic and no evidence against OR ≥ 3 reported cases as pathogenic and no evidence against, but with insufficient race-matched control data	No other LOF mutation reported as pathogenic and no evidence against
Class 3 (Uncertain)	CS^®/ESP MAF ≤ disease prevalence AND
Class 3 (Uncertain)	Novel missense or in-frame insertions, deletions	No LOF mutations reported as pathogenic OR inconsistent FHx	Single reported case as pathogenic and no supporting evidence OR multiple reported cases as pathogenic with evidence against	Single reported case as pathogenic with single evidence against OR multiple reported cases as pathogenic and multiple evidence against	Single reported case as VUS	Single reported case as benign with no supporting evidence
Class 2 (Likely not pathogenic)	ClinSeq^®/ESP MAF > disease prevalence OR
Class 2 (Likely not pathogenic)			Single reported case as pathogenic with multiple evidence against	Single reported case as pathogenic with multiple evidence against	Multiple evidence against pathogenic	Multiple cases reported as benign with no supporting evidence OR single report case as benign with supporting evidence
Class 1 (Benign)	MAF > 0.01 in ClinSeq^® or ESP or > 0.015 in dbSNP

Variants that passed quality and frequency filters were assigned to pathogenicity classes based on data available in HGMD, locus-specific databases, and family history (Figure 1). FHx, family history; ESP, National Heart Lung Blood Institute Exome Sequencing Project; LOF, loss of function; MAF, minor allele frequency; VUS, variants of unknown significance.