Table 5.

Annotation across protein domains of RYR2 and SCN5A

		Known missense variants			Paralogue mappings
Gene	Protein domains	Pathogenic	Benign	Uncertain	Actual	Enrichment
SCN5A	N-terminus	27	2	6	14	0.51
	Transmembrane	277	8	26	355	1.57
	Interlinker domains	99	25	35	41	0.31
	C-terminus	40	5	16	31	0.58
	Total	443	40	83	441
RYR2	Hotspots	134	10	17	157	1.52
	Outside hotspots	20	10	59	118	0.69
	Total	154	20	76	275

Distribution of known variants and paralogue mutation annotations across protein domains of SCN5A and mutation hotspots of RYR2. There is significant enrichment of both known pathogenic mutations and paralogue mutation mappings in the protein regions recognised to be susceptible to pathogenic variation, that is, the trans-membrane domains of SCN5A and the three mutation hotspots of RYR2.