We estimate the penetrance of LQTS for SCN5A c.3840+1G>A around 3% and the Brugada syndrome penetrance around 74%. SCN5A c.3840+1G>A was found in a total of 9 carriers in 17 papers and/or in gnomAD: 9 had Brugada syndrome, 0 had LQTS. c.3840+1G>A is not present in gnomAD. c.3840+1G>A has been functionally characterized in 17 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 (5 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 c.3840+1G>A around 3% (0/19) and the Brugada syndrome penetrance around 74% (14/19).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
NA	NA	NA	None	76	7

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
19251209	2009	1		0	1	0
17227473	2007	1		0	1	0
17404158	2007	2		0	2	0
18375968	2008	1		0	0	1	ARVC
20625312	2010	1		0	1	0
21273195	2011	4		0	4	0
22885917	2012	2		0	2	0
26173111	2015	1		0	1	0
26729854	2016	1		0	1	0
26921764	2016	2		0	2	0
28341781	2017	1		0	1	0
28781330	2017	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	2		0	2	0
29325976	2018	1		0	1	0
30059973	2018	5		5	0	0
30371189	2018	1		0	1	0
LITERATURE, COHORT, AND GNOMAD:	-	9	0	0	9		-
VARIANT FEATURES ALONE:	-	15	10	0	5	-	-

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
26173111	2015
26729854	2016
26921764	2016
28341781	2017
28781330	2017
20129283	2010
20129283	2010
29325976	2018
30059973	2018
30371189	2018
19251209	2009
17227473	2007
17404158	2007
18375968	2008
20625312	2010
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
1218	15	S1218I, S1218T,
1281	0	c.3840+1G>A, V1281F,
1304	9	T1304M,
1243	10	D1243N,
1274	11
1285	7
1299	10	c.3894delC,
1272	15
1298	14	P1298L,
1283	6	L1283M,
1309	12	R1309H, R1309C,
1288	11	A1288G,
1242	14
1251	12	V1251M,
1279	6	V1279I,
1306	8	R1306S, R1306H,
1244	14	K1244E,
1286	10
1305	7
1273	12	W1273C, c.3816delG,
1282	4	S1282A,
1246	13
1302	5	p.L1302Vfs18,
1247	9	T1247I,
1307	12
1289	13
1275	10	D1275N,
1222	14	L1222R, p.L1222LfsX7,
1300	11
1674	14	F1674V,
1254	12
1215	15	I1215V,
1301	9
1253	14	E1253G,
1284	5
1280	5
1308	12	L1308F,
1250	10
1240	14	E1240Q,
1248	13
1287	10
1276	9
1278	6	I1278N,
1249	13	V1249D,
1277	7
1303	8	R1303Q, R1303W,