Table 1.

Criteria for Age-based Semi-Quantitative Metric for Scoring Actionability

Category	Description	Score	Examples / details
SEVERITY “What is the effect on morbidity or mortality to an individual carrying a pathogenic variant in this gene?”	Sudden Death or Unavoidable Death in Childhood (<10yo)	3	Sudden death as a result of cardiac arrhythmia or aortic dissection; death before 10 years of age; other fatal infantile neurodegenerative conditions
	Possible Death due to disease or severe intellectual impairment	2	Cancer or multiple organ failure with potential for mortality; moderate to severe intellectual disability; loss of multiple senses
	Serious Morbidity or moderate intellectual impairment	1	Intellectual disability, growth disorders, non-fatal organ dysfunction
	Modest or No Morbidity	0	Benign biochemical phenotypes, later-onset neurosensory deficits
LIKELIHOOD “What is the chance that a threat will materialize?” (this is akin to penetrance, but may be scored for a single outcome of a condition)	≥ 50%	3	Likelihood is related to the chance that the outcome of interest will manifest. If likelihood information is not readily available, scores may be estimated through pedigree analysis and available segregation data. A score of 0 is assigned if there is little data available and likelihood cannot be reasonably estimated. Recessive conditions are typically assumed to have high penetrance unless evidence exists to the contrary.
	5–49%	2
	1–5%	1
	<1 %	0
EFFICACY “How effective are interventions for preventing the harm?”	Highly Effective	3	Completely prevents or substantially reduces morbidity in most patients
	Modestly Effective	2	Works relatively well, but still has some residual symptoms or potential for death
	Minimally Effective	1	Alleviates some symptoms, but not enough to effectively reduce or prevent morbidity. Also, may be able to treat some parts of the condition but not others.
	No Effective Intervention	0	Nothing can be done to prevent the morbidity in presymptomatic patients, typically assigned if interventions only relate to symptomatic management.
ACCEPTABILITY “How acceptable are the interventions in terms of the burdens or risks placed on the individual?”	Highly Acceptable	3	Little or no impact or burden. Yearly blood tests, noninvasive imaging screening tests, oral medications with low side effect profile
	Modestly Acceptable	2	Modest impact or burden. Invasive screening tests, daily lifestyle/diet modification, medications with substantial side effect profile
	Minimally Acceptable	1	Significant impact or burden. Removal of a non-vital organ or transplantation with frequent complications
	No Effective Intervention	0	Extreme impact or burden. Removal of a vital organ. Also assigned when no effective intervention is available
KNOWLEDGE “What is the evidence base for decisions about the natural history of the disease, and interventions used for preventing serious outcomes?”	Substantial Evidence and/or Practice Guidelines	3	Sufficient evidence to confidently score all categories for the specific gene-disease pair, based on high quality information from peer-reviewed journals, consensus statements, professional society practice guidelines.
	Modest Evidence	2	Sufficient evidence to score all categories, potentially based on inferences from a closely related condition or the molecular/biochemical mechanism of the disease, based on good quality information with minor limitations.
	Minimal Evidence	1	Unable to score one or more categories, due to limited information about the specific condition or closely related genes or phenotypes, with sparse primary literature.
	Controversial or Poor Evidence	0	Unable to reasonably score most or all categories due to controversial or minimal information about the specific condition, lack of primary literature, or conflicting information.
TOTAL		0–15