We estimate the penetrance of LQTS for SCN5A S1103Y around 1% and the Brugada syndrome penetrance around 0%. SCN5A S1103Y was found in a total of 2241 carriers in 13 papers and/or in gnomAD: 0 had Brugada syndrome, 17 had LQTS. S1103Y is present in 2134 alleles in gnomAD. S1103Y has been functionally characterized in 25 papers. This residue is located in a Non_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 (0 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 S1103Y around 1% (17/2251) and the Brugada syndrome penetrance around 0% (0/2251).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-1.82	0.268	-1.66	None	1	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
16453024	2006	1		0	0	1	SIDS
12193783	2002	27		13	0	1	Vtach
21385947	2011	1		0	0	1	SCD
12471205	2002	4		3	0	1	Vtach
16061744	2005	7		0	0	7	SD
20470418	2010	85		0	0	39	SIDS
20486126	2010	1		0	0	1	SIDS
21964171	2011	1		0	0	1	SUDS
22677073	2012	4		0	0	4	SUDS
23714088	2013	1		1	0	0
25757662	2015	1		0	0	1	SIDS
20129283	2010	31		0	0	0
29907895	2018	3		0	0	3	SIDS
LITERATURE, COHORT, AND GNOMAD:	-	2241	2224	17	0		-
VARIANT FEATURES ALONE:	-	15	15	0	0	-	-

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)
20486126	2010
21964171	2011
22677073	2012
23714088	2013
18452875	2008
18452876	2008
21498565	2011
24332150	2014
25065297	2014
15992733	2005
16453014	2006
20451667	2010
25757662	2015	HEK
20129283	2010
15992732	2005	HEK	85	-3	-3
16453024	2006	HEK	111	0.6	-0.4
12193783	2002	HEK	114	-4.5		38
21385947	2011	HEK	132	-6.1	-4.6	165
29907895	2018
12471205	2002
15851227	2004
15898185	2004
16061744	2005
20403459	2010
20470418	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
1088	15	A1088V, A1088T,
1089	14
1090	14	P1090Q, P1090L,
1091	13	D1091A, D1091Y,
1092	13
1093	12
1094	11
1095	11	W1095C, W1095X,
1096	10	S1096G, S1096C,
1097	9	Q1097H, c.3288+2delT,
1098	8	V1098M, V1098L,
1099	8
1100	7	A1100T, A1100V,
1101	5
1102	4	A1102T,
1103	0	S1103F, S1103Y,
1104	4
1105	5	E1105V, E1105X,
1106	7	A1106T,
1107	8	p.E1107RfsX24, E1107K, E1107X,
1108	8
1109	9	S1109G,
1110	10
1111	11
1112	11	Q1112X,
1113	12	A1113T, A1113V,
1114	13	D1114N, D1114E,
1115	13	W1115R, W1115X,
1116	14	R1116W, R1116Q,
1117	14
1118	15	Q1118X,