We estimate the penetrance of LQTS for SCN5A I1660V around 11% and the Brugada syndrome penetrance around 34%. SCN5A I1660V was found in a total of 17 carriers in 11 papers and/or in gnomAD: 5 had Brugada syndrome, 2 had LQTS. I1660V is present in 8 alleles in gnomAD. I1660V has been functionally characterized in 11 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 (4 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 I1660V around 11% (2/27) and the Brugada syndrome penetrance around 34% (9/27).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-0.89	0.986	4.88	0.837	60	6

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
24269159	2013	2		0	1	0
17075016	2006	3		0	1	0
16414944	2005	1		1	0	0
20812931	2011	1		0	1	0
23631430	2013	1		1	0	0
26173111	2015	1		0	1	0
20129283	2010	4		0	4	0
20129283	2010	4		0	4	0
29709244	2018	2		0	1	0
29759671	2018	1		0	1	0
30059973	2018	2		2	0	0
LITERATURE, COHORT, AND GNOMAD:	-	17	10	2	5		-
VARIANT FEATURES ALONE:	-	15	11	0	4	-	-

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)
16414944	2005
20812931	2011
23631430	2013
26173111	2015
20129283	2010
20129283	2010
29709244	2018
29759671	2018
30059973	2018
24269159	2013	HEK	0
17075016	2006	HEK-tSA201	3	NA	NA	0

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	11
1328	14	V1328M,
1659	5
1773	14
1765	10
1653	10
1472	15	p.N1472del, N1472S,
1315	12
1771	11	I1771T,
401	14	S401P,
1652	15	M1652R, M1652T,
1314	10	c.3940_3941delCT,
1320	7	M1320I,
1764	8	c.5290delG, V1764F,
1666	11
1650	14	L1650F,
1656	6
1477	14	K1477N,
1762	10	p.I1762del, I1762M,
1470	14
1668	12	M1668T,
1466	14	c.4396_4397insG,
1767	6	Y1767C,
1313	14
1660	0	I1660S, I1660V,
1654	11
1769	10
402	10	F402L,
1766	6	M1766V, M1766T, M1766L,
1319	9	G1319V,
1665	11
1768	10	I1768V,
1774	14	c.5321_5324dupACTT, N1774D,
1473	11	F1473S, F1473C,
1663	5
399	12
397	14	I397F, I397T, I397V,
1657	6
1759	10	S1759C,
1662	7
1324	10
1317	11	F1317C,
1327	10
1709	14	T1709M, p.T1709del, T1709R,
1758	12	p.I1758del, I1758V,
1755	14
1318	13
1330	15	A1330T, A1330D, A1330P,
1772	14	L1772V,
1321	13	R1321K,
1323	6	V1323G,
394	13
1770	8	I1770V,
1708	12	T1708I,
1705	14
1322	10	c.3963+4A>G, c.3963+2T>C,
1326	11	A1326S,
1763	6	V1763M, V1763L,
1311	13	L1311P,
1760	14
1476	14	Q1476X, Q1476R,
1670	15
1661	4	G1661R, G1661E,
1761	14	L1761F, L1761H, c.5280delG,
1655	9
1469	12	I1469V,
406	13	N406K, N406S,
1325	13	N1325S,
398	9
400	14	G400R, G400A, G400E,
1667	10	V1667I,
1664	6
1658	8