We estimate the penetrance of LQTS for SCN5A E161K around 6% and the Brugada syndrome penetrance around 68%. SCN5A E161K was found in a total of 13 carriers in 12 papers and/or in gnomAD: 11 had Brugada syndrome, 1 had LQTS. E161K is present in 1 alleles in gnomAD. E161K has been functionally characterized in 15 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 E161K around 6% (1/23) and the Brugada syndrome penetrance around 68% (15/23).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-3.45	0.999	-2.88	0.961	67	2

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
15910881	2005	11		0	9	2	SSS, conduction disease
12106943	2002	1		0	1	0
16764707	2006	10		0	10	0
19843921	2009	1		0	1	0
20031634	2009	11		0	7	0
20386770	2010	1		1	0	0	AV block
21273195	2011	8		0	8	0
19251209	2009	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
29574140	2018	1		0	1	0
30059973	2018	2		2	0	0
LITERATURE, COHORT, AND GNOMAD:	-	13	1	1	11		-
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)
29574140	2018
30059973	2018
12106943	2002
16764707	2006
19843921	2009
20031634	2009
20386770	2010
21273195	2011
20539757	2010
19251209	2009
15878172	2005
20129283	2010
20129283	2010
15910881	2005	tsA201	40	11.9	0.9
20384651	2010	HEK	23	19.1	1.9

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
154	13	P154L,
223	13	V223L,
859	14
153	15
149	13
147	7
164	6	F164L,
209	14	N209T, N209S,
143	11
156	9	W156X, W156R,
158	6	K158T,
163	7	c.486delC,
216	15	S216X, S216L,
169	13
222	8	R222L, R222Q, R222X,
155	11
150	12
157	7	T157I,
160	5	p.V160fs,
205	12	Y205X, c.612-2A>G,
206	13
166	10	A166T,
144	8
855	15
148	10
165	7
210	13	I210T,
204	9	A204V, A204T, c.611+3_611+4dupAA, c.611+1G>A,
162	5	Y162H, Y162C,
146	13	V146A, V146M,
203	13
208	8	E208K,
168	10
202	15	I202T,
152	15	D152N,
141	13	I141N, I141V,
167	11
161	0	E161Q, E161K,
201	12
219	9	c.656_657insATTCA, R219H, R219C, p.R219HfsX11,
225	13	R225Q, R225W,
151	9
218	12
159	7	Y159C, Y159X,
207	9
212	14	L212Q, L212P,
200	13
145	12
140	12
220	14	T220I,