Table 1.

DCM Precision Medicine Study Variant Interpretation Criteria

Strength	Specification type	Rule abbreviation	Rule description
Pathogenic criteria
Very strong	Reintroduced ACMG criterion for DCM gene specification	PVS1	Null variant in LMNA or SCN5A
Strong	none	PS1	Same amino acid change as a previously established pathogenic variant
	none	PS2	De novo (paternity confirmed) in a patient with disease and no family history
	none	PS3	Well-established in vitro or in vivo functional studies supportive of a damaging effect
	none	PS4	Prevalence of variant in affected individuals is significantly increased compared to controls OR variant identified in ≥15 probands with consistent phenotypes OR variant identified in ≥10 confirmed unlreated probands with consistent phenotypes
	none	PP1_Strong	Variant segregates in ≥7 meioses in DCM genes with established evidence
	Strength modification, DCM gene specification	PVS1_Strong	Null variant in FLNC, BAG3,and TTN A-band
Moderate	DCM gene specification	PM1	Located in hotspot (For DCM, RBM20 exon 9, amino acids 634, 636, 637, 638)
	DCM gene specification, study specific	PM2	Absent from gnomAD or at extremely low frequency in all gnomAD non-founder populations with available data
	Reintroduced ACMG criterion, DCM gene specification	PM3	For recessive disorders, detected in transwith a pathogenic variant (rarely observed with TNNI3 and TNNT2 variants)
	none	PM4	In-frame deletions/insertions of any size in a non-repeat region or stop-loss variants
	none	PM5	Different missense change at same amino acid residue previously established as pathogenic
	DCM specific	PM6	De novo without confirmation of paternity (parental clinical data required)
	DCM gene specification	PVS1_Moderate	Null variant in gene with evidence supporting loss of function as disease mechanism (VCL, PLN, DSP)
	none	PS4_Moderate	Variant identified in ≥6 probands with consistent phenotypes
	none	PP1_Moderate	Variant segregates in ≥5 meioses in DCM genes with established evidence
Supporting	none	PP1	Variant segregates in ≥3 meioses in DCM genes with established evidence
	Method specification	PP3	Computational evidence support a deleterious effect (REVEL score >0.7)
	none	PS4_Supporting	Variant identified in ≥2 probands with consistent phenotypes
Benign
Stand alone	none	BA1	Variant allele frequency is >0.1% in any gnomaAD non-founder population
	DCM gene specification	BP1_Stand_Alone	Missense variant in TTN
Strong	DCM gene specification, study specific	BS1	Variant allele frequency is >0.05% in any gnomAD non-founder population
	none	BS3	Well established in vitroor in vivo functional studies show no damaging effect
	none	BS4	Non-segregation in affected members of a family
Supporting	none	BP2	Observed as a compound heterozygote (in trans) or double heterozygote in genes with overlapping function
	Method specification	BP4	Multiple lines of computational evidence suggest no impact on gene or gene product (REVEL score <0.15)
	Study specific	BP7	Unlikely to affect protein function based on calculated Sequence Ontology terms for the transcript(s) of interest.