We estimate the penetrance of LQTS for SCN5A M1766L around 66% and the Brugada syndrome penetrance around 16%. SCN5A M1766L was found in a total of 1 carriers in 5 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. M1766L is not present in gnomAD. M1766L has been functionally characterized in 7 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 M1766L around 66% (3/11) and the Brugada syndrome penetrance around 16% (1/11).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-2.74	0.863	5.17	0.935	12	64

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
12123767	2002	2		1	0	1	2:1 AV block
15840476	2005	1		1	0	0
25904541	2015	1		1	0	0
27566755	2016	1		1	0	0
30059973	2018	1		1	0	0
LITERATURE, COHORT, AND GNOMAD:	-	1	0	1	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)
12123767	2002	HEK-tSA201	10	7	9	4000
15840476	2005
12123759	2002
25904541	2015
27566755	2016
30059973	2018
12454206	2003	HEK	20

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	11	V1328M,
1659	11
1773	11
1765	6
1653	12
1757	11
1472	9	p.N1472del, N1472S,
1315	14
1771	10	I1771T,
1756	14	I1756V,
1314	14	c.3940_3941delCT,
1320	10	M1320I,
1764	6	c.5290delG, V1764F,
1666	14
409	15	L409P, L409V,
1333	13
1656	10
1477	12	K1477N,
1471	12
935	15	L935P,
1762	6	p.I1762del, I1762M,
1470	9
1464	14	L1464P, c.4389_4396delCCTCTTTA,
1466	9	c.4396_4397insG,
1767	7	Y1767C,
1660	6	I1660V, I1660S,
1654	15
1329	11	G1329S,
1769	6
402	11	F402L,
1766	0	M1766L, M1766V, M1766T,
1319	12	G1319V,
1768	7	I1768V,
1774	13	c.5321_5324dupACTT, N1774D,
1473	6	F1473C, F1473S,
1334	11	I1334V,
1468	10	V1468F, V1468A,
1663	9
1462	15
1657	9
1474	13
1759	9	S1759C,
1662	12
1324	9
1327	7
1709	14	T1709M, T1709R, p.T1709del,
1758	10	p.I1758del, I1758V,
1755	14
1330	9	A1330P, A1330T, A1330D,
1772	11	L1772V,
1323	7	V1323G,
1770	7	I1770V,
1708	13	T1708I,
1322	10	c.3963+4A>G, c.3963+2T>C,
1326	7	A1326S,
1763	4	V1763M, V1763L,
1332	14	P1332L, P1332Q,
1465	11	p.F1465_L1480dup,
1760	11
1467	11
1476	11	Q1476X, Q1476R,
1661	10	G1661E, G1661R,
1331	11	I1331V,
1761	10	c.5280delG, L1761F, L1761H,
1655	14
1475	14	p.Q1475NfsX6, Q1475L,
1469	6	I1469V,
406	12	N406K, N406S,
1325	11	N1325S,
398	13
1667	12	V1667I,
1664	10
1463	14	N1463Y,
1658	13