We estimate the penetrance of LQTS for SCN5A V1763M around 82% and the Brugada syndrome penetrance around 7%. SCN5A V1763M was found in a total of 7 carriers in 8 papers and/or in gnomAD: 0 had Brugada syndrome, 7 had LQTS. V1763M is not present in gnomAD. V1763M has been functionally characterized in 8 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a 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 (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A V1763M around 82% (9/17) and the Brugada syndrome penetrance around 7% (1/17).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-2.77	0.999	6.04	0.951	17	71

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
23998552	2013	1		1	0	0
15485686	2004	2		1	0	1	2:1 AV block
15840476	2005	1		1	0	0
16379539	2005	1		1	0	0
22360817	2012	2		2	0	0
27566755	2016	2		2	0	0
19716085	2009	1		1	0	0
30059973	2018	6		6	0	0
LITERATURE, COHORT, AND GNOMAD:	-	7	0	7	0		-
VARIANT FEATURES ALONE:	-	15	12	2	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)
15485686	2004	HEK-tSA201	120	-3.8	11.5	333
30059973	2018
15840476	2005
16379539	2005
22360817	2012
27566755	2016
19716085	2009
23998552	2013	hiPSC-CM	83	2.76	16.75	486

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
403	14
1328	12	V1328M,
1659	11
1765	6
1653	15
1757	9
1472	13	N1472S, p.N1472del,
1315	14
1771	13	I1771T,
401	14	S401P,
1756	11	I1756V,
1314	13	c.3940_3941delCT,
1320	11	M1320I,
1764	4	V1764F, c.5290delG,
1666	11
371	15	Q371E,
1333	15
1754	12
1707	13
1656	12
1704	13	L1704H,
1671	13
1762	5	p.I1762del, I1762M,
1470	13
1668	11	M1668T,
1466	11	c.4396_4397insG,
1753	15	T1753A,
1767	8	Y1767C,
1660	6	I1660V, I1660S,
1329	13	G1329S,
1769	10
402	10	F402L,
1766	4	M1766V, M1766T, M1766L,
1319	14	G1319V,
1665	13
1768	9	I1768V,
1473	11	F1473C, F1473S,
1334	12	I1334V,
1468	13	V1468A, V1468F,
1663	7
397	14	I397F, I397T, I397V,
1462	14
1657	10
1759	5	S1759C,
1662	11
1324	11
1327	8
1709	11	T1709R, T1709M, p.T1709del,
1758	6	p.I1758del, I1758V,
1755	9
1330	11	A1330D, A1330T, A1330P,
1772	14	L1772V,
1713	15
1323	9	V1323G,
1770	11	I1770V,
1708	9	T1708I,
1705	14
1322	13	c.3963+4A>G, c.3963+2T>C,
1326	10	A1326S,
1763	0	V1763L, V1763M,
1311	14	L1311P,
1465	11	p.F1465_L1480dup,
1760	8
1467	13
1670	14
1661	9	G1661E, G1661R,
1331	12	I1331V,
1761	8	L1761H, c.5280delG, L1761F,
1469	9	I1469V,
406	13	N406K, N406S,
1710	13	S1710L,
1325	14	N1325S,
398	12
1667	9	V1667I,
1664	6
1463	15	N1463Y,
1658	13