Table 3 CNV classification using ACMG/ClinGen framework.

Family	Diagnosis	CNV class	Clinically relevant gene	Interpretation of CNV	ACMG/ClinGen Criteria (score)	Total Score	Classification
CMD	HCM	Intergenic deletion	MYBPC3	ClinGen haploinsufficiency score 3; nonspecific phenotype consistent with similar cases	2D-4 (0.9) 5G (0.1)	1.0	Pathogenic
NSW76A	SUD	Intergenic deletion	KCNH2	ClinGen haploinsufficiency score 3; nonspecific phenotype consistent with similar cases	2A (1.0) 5G (0.1)	1.1	Pathogenic
CBD	DCM	Intragenic deletion	TTN	De novo truncating variant in our patient and in literature; truncating variant burden in DCM; multiple segregations reported for truncating variants	4C (0.1) 4M (0.45) 4H (0.45) 5A (0.15)	1.15	Pathogenic
AHM	LVNC	Intragenic deletion	ACTN2	Truncating variant burden in LVNC; nonspecific phenotype consistent with similar cases	4M (0.3) 5G (0.1)	0.4	VUS
AYQ	HCM	Tandem partial-gene duplication	MYH7	Similarly affected family members with 7 segregations; nonspecific phenotype consistent with similar cases	4H (0.45) 5G (0.1)	0.55	VUS
CBT	LVNC	Duplication	RBM20	Truncating variant burden in LVNC; nonspecific phenotype consistent with similar cases	4M (0.3) 5G (0.1)	0.4	VUS
BLX	LQTS	Duplication	PLN	No supporting criteria	NA	0	VUS
CIJ	DCM	Intragenic deletion	CTNNA3	Overlap with common population variation	4O (−1.0)	−1	Benign

2A: CNV overlaps established haploinsufficiency locus; 2D-4: CNV overlaps established haploinsufficiency locus that includes other exons in addition to the last exon—nonsense-mediated decay is expected to occur; 4C: previously reported proband has a phenotype consistent with the haploinsufficiency gene of interest where phenotype is not highly specific; 4H: seven or more observed segregations among affected family members in literature; 4M: statistically significant increase in cases (with nonspecific phenotype) compared with population controls; 4O: CNV overlaps with a common population variation reported in public databases; 5A: CNV arises de novo in proband; 5G: inheritance information is unavailable and patient phenotype is consistent with previous reports but it is nonspecific.
ACMG American College of Medical Genetics and Genomics, CNV copy-number variant, DCM dilated cardiomyopathy, HCM hypertrophic cardiomyopathy, LQTS long QT syndrome, LVNC left ventricular noncompaction, SUD unexplained sudden cardiac death VUS variant of uncertain significance.

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