We estimate the penetrance of LQTS for SCN5A I1768V around 68% and the Brugada syndrome penetrance around 2%. SCN5A I1768V was found in a total of 31 carriers in 11 papers and/or in gnomAD: 0 had Brugada syndrome, 22 had LQTS. I1768V is not present in gnomAD. I1768V has been functionally characterized in 16 papers. This residue is located in a Non_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 (0 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 I1768V around 68% (24/41) and the Brugada syndrome penetrance around 2% (0/41).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-0.93	1	5.57	0.9	7	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
12650885	2003	1		1	0	0
12566525	2003	1		1	0	0
17905336	2007	1		1	0	0
22677073	2012	1		0	0	1	SUDS
23683917	2013	1		0	0	1	SUD
25804018	2014	2		2	0	0
26669661	2016	27		18	0	0
25904541	2015	3		3	0	0
27566755	2016	58		58	0	0
12209021	2002	1		1	0	0
30059973	2018	9		9	0	0
LITERATURE, COHORT, AND GNOMAD:	-	31	9	22	0		-
VARIANT FEATURES ALONE:	-	15	13	2	0	-	-

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)
12695286	2003	HEK	100			100
12650885	2003	Xeno	102	0.7	0.9	94
30059973	2018
12566525	2003
16829642	2006
17905336	2007
22677073	2012
23683917	2013
25804018	2014
26669661	2016
29017927	2017
17556201	2007
25904541	2015
27566755	2016
17556202	2007
12209021	2002	HEK		0	7.6	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	9
414	15	M414V,
939	12	L939F,
1659	14
404	11	L404Q, L404V,
1773	9
1765	5
1653	11
1472	12	p.N1472del, N1472S,
1771	6	I1771T,
401	10	S401P,
1652	15	M1652T, M1652R,
1764	7	c.5290delG, V1764F,
371	13	Q371E,
409	8	L409P, L409V,
928	13	L928P,
1650	12	L1650F,
1656	12
934	15
1477	14	K1477N,
933	15
1471	12
935	10	L935P,
412	13	V412D,
1762	10	p.I1762del, I1762M,
1470	7
1464	13	L1464P, c.4389_4396delCCTCTTTA,
927	14	N927S, N927K,
1466	6	c.4396_4397insG,
1776	13
369	14	M369K,
1767	6	Y1767C,
1660	10	I1660V, I1660S,
1654	14
1769	4
402	8	F402L,
1766	7	M1766L, M1766V, M1766T,
1649	14	A1649V,
1768	0	I1768V,
1774	11	N1774D, c.5321_5324dupACTT,
1473	9	F1473C, F1473S,
1468	11	V1468F, V1468A,
1663	14
399	14
397	14	I397V, I397F, I397T,
405	8
1657	10
1462	13
1474	13
1759	12	S1759C,
938	14
1327	14
1709	13	p.T1709del, T1709M, T1709R,
1758	15	p.I1758del, I1758V,
1330	15	A1330T, A1330P, A1330D,
1772	6	L1772V,
1323	13	V1323G,
410	9	A410V,
1770	7	I1770V,
1658	14
1708	14	T1708I,
413	12	A413E, A413T,
408	11
1322	15	c.3963+4A>G, c.3963+2T>C,
407	10
1326	13	A1326S,
936	12
1763	9	V1763L, V1763M,
1465	12	p.F1465_L1480dup,
1760	11
1467	10
1775	12	p.F1775LfsX15, F1775V,
370	15	T370M,
1661	13	G1661E, G1661R,
1761	11	L1761H, c.5280delG, L1761F,
1655	15
1469	8	I1469V,
406	5	N406K, N406S,
1710	15	S1710L,
411	13	V411M,
932	10
398	12
400	12	G400A, G400E, G400R,
931	14
1664	13
1463	11	N1463Y,