We estimate the penetrance of LQTS for SCN5A D1275N around 1% and the Brugada syndrome penetrance around 13%. SCN5A D1275N was found in a total of 28 carriers in 17 papers and/or in gnomAD: 3 had Brugada syndrome, 0 had LQTS. D1275N is present in 2 alleles in gnomAD. D1275N has been functionally characterized in 24 papers. This residue is located in a Mild_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 (1 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 D1275N around 1% (0/38) and the Brugada syndrome penetrance around 13% (4/38).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-4.87	1	-2.2	0.935	21	5

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
28637969	2017	1		0	0	1	AV conduction block
12522116	2003	8		0	0	3	Atrial standstill
15466643	2004	8		0	0	8	Dilated Cardiomyopathy
15671429	2005	22		0	0	7	DCM
16684018	2006	1		0	0	1	conduction defect, atrial arrythmia
24762805	2014	4		0	0	2	SSS
26111534	2015	1		0	0	1	SND, AF
26798387	2016	2		0	0	2	SSS
27707468	2016	1		0	1	0
19251209	2009	1		0	1	0
26746457	2016	1		0	0	0
28294644	2017	13		0	0	13	BBBlock, AF
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
29325976	2018	1		0	1	0
29579189	2018	1		0	0	1	Afib
30059973	2018	4		4	0	0
LITERATURE, COHORT, AND GNOMAD:	-	28	25	0	3		-
VARIANT FEATURES ALONE:	-	15	14	0	1	-	-

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)
24573164	2014	HEK	88		-0.84
12522116	2003	Xeno	89	3.3	-0.7
15466643	2004
15671429	2005
20384651	2010		68	3	1
15671436	2005
24762805	2014
16684018	2006
26111534	2015
26798387	2016
20539757	2010
19251209	2009
21824921	2011
23791817	2013
27707468	2016
28294644	2017
15998690	2005
26746457	2016
20129283	2010
20129283	2010
29325976	2018
29579189	2018
30059973	2018
28637969	2017	HEK	77	10.1	2

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
1267	10
1271	8	W1271C,
1218	14	S1218T, S1218I,
1281	10	c.3840+1G>A, V1281F,
1304	13	T1304M,
1315	14
1274	4
1216	14	L1216V,
1258	10
1272	6
1270	9	A1270S,
1252	12
1283	12	L1283M,
1309	5	R1309H, R1309C,
1265	15
1219	15	S1219N,
1251	11	V1251M,
1313	12
1279	7	V1279I,
1310	10
1316	14	R1316L, R1316Q,
1207	14
1306	9	R1306S, R1306H,
1305	9
1273	8	c.3816delG, W1273C,
1246	13
1282	11	S1282A,
1302	14	p.L1302Vfs18,
1262	14	G1262S,
1247	12	T1247I,
1257	8
1268	13	T1268N, T1268S,
1307	11
1256	12
1275	0	D1275N,
1255	12	L1255M,
1254	7
1215	10	I1215V,
1260	15	A1260D,
1263	14
1214	13	M1214T,
1212	12	p.I1212del,
1253	8	E1253G,
1284	15
1211	10
1312	10
1280	9
1311	11	L1311P,
1308	9	L1308F,
1250	7
1269	9	N1269S,
1276	7
1278	5	I1278N,
1266	8
1261	12
1249	11	V1249D,
1208	13	E1208K, E1208X,
1277	7
1303	14	R1303W, R1303Q,