We estimate the penetrance of LQTS for SCN5A R878C around 0% and the Brugada syndrome penetrance around 83%. SCN5A R878C was found in a total of 36 carriers in 9 papers and/or in gnomAD: 32 had Brugada syndrome, 0 had LQTS. R878C is not present in gnomAD. R878C has been functionally characterized in 12 papers. This residue is located in a Hotspot region for Brugada syndrome and a Non_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (6 diagnosed with Brugada syndrome) and 5 individuals for LQTS (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A R878C around 0% (0/46) and the Brugada syndrome penetrance around 83% (38/46).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-7.6	1	-5.06	0.961	93	0

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance Density is our previously published method to calculate the average BrS/LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

PubMed ID	Year	Carriers	Unaffected	LQT3	BrS1	Other	Other Disease
18616619	2008	4		0	3	0
22840528	2012	1		0	1	0
24721456	2014	2		0	2	0
26036855	2016	11		0	11	0
28341781	2017	1		0	1	0
28781330	2017	30		0	27	0
20129283	2010	1		0	1	0
29325976	2018	1		0	1	0
30059973	2018	1		1	0	0
LITERATURE, COHORT, AND GNOMAD:	-	36	4	0	32		-
VARIANT FEATURES ALONE:	-	15	9	0	6	-	-

Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V_0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.

PubMed ID	Year	Cell Type	Peak Current (%WT)	V1/2 Act. (mV)	V1/2 Inact. (mV)	Late/Persistent Current (%WT)
29325976	2018
30059973	2018
20384651	2010		0
22739120	2012	HEK	0
18616619	2008	HEK	0
22840528	2012
24721456	2014
26036855	2016
28341781	2017
28781330	2017
20539757	2010
20129283	2010

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor	Distance (Angstroms)	Variants Observed in Individuals
880	9
888	15
890	11	I890T,
901	9	S901L, E901K,
1430	10	D1430N,
1426	5
894	15	I894M,
1447	14
1444	12	L1444I,
1440	7	W1440X,
1380	14	p.N1380del, N1380K,
1429	10
1442	15	Y1442N, Y1442C,
1450	15
887	13
886	9	H886Q, H886P,
1362	13	R1362S, c.4083delG,
1438	14	P1438L,
871	13
1423	7	D1423H,
876	9
1431	14	S1431C,
1422	7	M1422R,
902	11
882	14
892	15	F892I,
881	13
898	12
893	10	R893H, R893C,
889	10
1420	11	G1420R, G1420D, G1420V, G1420P,
900	14
1360	15	F1360C,
872	13	D872N,
1425	9
865	13
1427	10	A1427E, A1427S,
1424	11	I1424V,
1439	13	Q1439H, Q1439R,
906	14
874	12	G874D,
878	0	R878C, R878L, R878H,
1421	11
885	14
350	15	H350Q,
1441	11	E1441Q,
877	6
879	4	W879R,
883	14
905	11
875	12
1428	12	A1428V, A1428S,
908	15
873	14	S873A,
1419	15	K1419E,