Table 2.

Reasons to lump or split gene-disease assertions

Reasons to lump	Reasons to split
An assertion for only 1 disease entity has been made in the literature	An assertion for >1 distinct disease entity has been made in the literature
No difference in molecular mechanism is observed among the disease entities	A well-established difference in molecular mechanism(s) between ≥2 disease entities is observed
Interfamilial phenotypic variability is no more pronounced than intrafamilial variability	Interfamilial phenotypic variability is more pronounced than intrafamilial variability
The difference in the inheritance pattern for the disease entities is representative of a continuum of disease (i.e., mild phenotypic features are observed in heterozygotes for recessive disease or dosage impacts are observed for dominant disease [more severe phenotype in homozygotes])	The representative disease entities between differing inheritance patterns are distinguishable, with notable varying phenotypes and/or clinical management distinctions
The disease entities in question are seemingly part of a variable phenotype observed within a single organ system and there is insufficient evidence for any single phenotype •If variants for each entity are VUSs, and no distinguishing phenotype is observed, then lump for a broader phenotype	To dispute or refute a disease entity assertion for the gene in question •Must have convincing evidence to dispute or refute •This would be a very rare occurrence, and the isolated disease entity being disputed or refuted cannot be included as part of the phenotypic spectrum observed in a syndrome associated with the gene of interest