Table 1.

Rare LMNA and MYBPC3 missense, synonymous, and intronic variants that alter RNA splicing

		All reported variants		LMM and ClinVar					ExAC only
Gene	Predictedeffect	Total variants	Splice altering candidates	Variants affecting splicing	Pathogenic	Likely pathogenic	VUS	Benign	Variants affecting splicing
LMNA	Acceptor loss	45	5	5	1	1	3	0	0
	Donor loss	25	8	3	1	0	2	0	0
	Acceptor gain	745	25	0	0	0	0	0	0
	Donor gain		19	5	3	1	1	0	1
	Total	815	57	13	5	2	6	0	1
MYBPC3	Acceptor loss	126	30	11	1	3	7	0	2
	Donor loss	69	36	19	6	3	10	0	1
	Acceptor gain	1,380	32	3	0	1	2	0	0
	Donor gain		41	2	0	0	2	0	1
	Total	1,575	139*	35	7	7	21	0	4

Of the 815 rare LMNA variants, 57 were computationally predicted to alter normal splicing patterns. Among 14 of 57 LMNA splice candidates that altered splicing in the cell assay, 13 are reported in clinical databases as classified as indicated. One functional variant reported only in the ExAC database is not clinically classified. Of the 1,575 rare MYBPC3 variants, 139 were computationally predicted to alter normal splicing. Among 39 MYBPC3 splice candidates that altered splicing in the cell assays, 35 are reported in clinical databases as classified as indicated. Four functional variants reported only in the ExAC database are not clinically classified.

^*MYBPC3 c.2905+5G > T was predicted to cause multiple splicing changes. Independent constructs and cell assays were performed to evaluate whether the variant caused a donor loss or acceptor gain (Dataset S4). Cell assays only showed the variant functioned as a donor site loss that significantly altered splicing.