Table 1.

Variant classification	Criteria
Pathogenic	Predicted null variant in gene where loss of function is known disease mechanism; de novo variant; absent in population databases or MAF very low; co-segregation in multiple families; computational predictions support deleterious effect; functional data support deleterious effect
Likely Pathogenic	Criteria similar to pathogenic but with less supporting evidence such as fewer available families for co-segregation data, contradictory computational predictions or weaker functional data
Variant Uncertain Significance	Very low population frequency or absent from databases but lacking co-segregation, computational, and/or functional evidence for pathogenicity
Likely Benign	Allele frequency greater than expected for disease incidence; allele identified in young, healthy individuals; no effect in functional assays; lack of segregation in family members; and/or mutation type not consistent with known disease mechanism
Benign	MAF >5% in ExAC or ESP OR 2 or more of the likely benign criteria

ESP, Exome Sequencing Project; ExAC, Exome Aggregation Consortium; MAF, minor allele frequency. For detailed criteria, see Richards et al. (32)