We estimate the penetrance of LQTS for SCN5A G1743E around 3% and the Brugada syndrome penetrance around 73%. SCN5A G1743E was found in a total of 10 carriers in 14 papers and/or in gnomAD: 10 had Brugada syndrome, 0 had LQTS. G1743E is not present in gnomAD. G1743E has been functionally characterized in 14 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 (4 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 G1743E around 3% (0/20) and the Brugada syndrome penetrance around 73% (14/20).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-7.4	1	-2.44	0.983	60	3

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
16945804	2006	2		0	2	0
12106943	2002	1		0	1	0
16764707	2006	5		0	5	0
17404158	2007	1		0	1	0
19843921	2009	1		0	1	0
21273195	2011	8		0	8	0
22885917	2012	6		0	6	0
26921764	2016	2		0	2	0
19251209	2009	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
29325976	2018	2		0	2	0
29325976	2018	2		0	2	0
30059973	2018	8		8	0	0
LITERATURE, COHORT, AND GNOMAD:	-	10	0	0	10		-
VARIANT FEATURES ALONE:	-	15	11	0	4	-	-

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)
22885917	2012
26921764	2016
19251209	2009
20129283	2010
20129283	2010
29325976	2018
29325976	2018
30059973	2018
16945804	2006	HEK	0
12106943	2002
16764707	2006
17404158	2007
19843921	2009
21273195	2011

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
1746	10	A1746T, A1746V,
1724	12
1741	7	D1741E, D1741N, D1741Y,
1715	14
1687	15
1726	15
1745	7
1675	12
1743	0	G1743R, G1743E,
1723	11	T1723N,
1725	11	P1725L,
1681	11	c.5040_5042delTTAinsC, Y1681F,
1694	12
1747	8	V1747M,
1716	13	p.L1716SfsX71,
1695	14	Q1695X,
1688	13
1684	13	W1684R,
1676	14	M1676T, M1676I,
1744	4	S1744I,
1721	7
1742	4
1733	13
1693	14
1738	14	S1738T, S1738F,
1680	9	A1680P, A1680T,
1727	14
1719	8
1731	8
1728	10	C1728R, C1728Y, C1728W,
1678	9	N1678S,
1300	15
1674	15	F1674V,
1399	13
1748	9	p.G1748del, G1748D,
1730	12	P1730H, P1730A, P1730L,
1683	7
1718	11	S1718R,
1739	11	R1739W, R1739Q,
1717	11	L1717P,
1734	14
1751	13
1677	12
1682	6
1750	14	L1750F,
1752	14
1722	6	N1722D,
1686	14
1749	12	I1749N,
1729	12	D1729N,
1740	7	G1740R,
1720	6	c.5157delC,
1732	9
1679	8
1685	11