We estimate the penetrance of LQTS for SCN5A L1501V around 57% and the Brugada syndrome penetrance around 13%. SCN5A L1501V was found in a total of 22 carriers in 11 papers and/or in gnomAD: 3 had Brugada syndrome, 13 had LQTS. L1501V is present in 5 alleles in gnomAD. L1501V has been functionally characterized in 13 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 (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 L1501V around 57% (15/32) and the Brugada syndrome penetrance around 13% (4/32).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-2.76	0.999	0	0.854	9	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
10973849	2000	1		1	0	0
20102864	2010	1		0	0	1	SUD
22840528	2012	1		0	1	0
23631430	2013	1		1	0	0
24721456	2014	1		0	1	0
28494446	2017	2		0	1	0
25904541	2015	1		1	0	0
27566755	2016	13		13	0	0
19716085	2009	1		1	0	0
20129283	2010	1		0	1	0
30059973	2018	4		4	0	0
LITERATURE, COHORT, AND GNOMAD:	-	22	6	13	3		-
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)
27566755	2016
19716085	2009
20129283	2010
30059973	2018
24573164	2014	HEK	100		0.19
10973849	2000
20102864	2010
22840528	2012
23631430	2013
24721456	2014
28494446	2017
29017927	2017
25904541	2015

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
1850	9	C1850S,
1855	7
1785	12
1794	10
1849	12	H1849R,
1856	9
1853	10	I1853V,
1795	10	Y1795N, Y1795C, p.Y1795_E1796insD, Y1795H,
1880	14	M1880V,
1824	14	P1824A,
1838	15
1492	14
1504	7	K1504E,
1491	15	Q1491H,
1851	7	M1851V, M1851I,
1501	0	p.L1501_K1505del, L1501V,
1860	14	c.5577_5578dupAA,
1857	11
1862	12
1493	14	p.K1493del, K1493R, K1493X,
1505	11	K1505N, p.K1505_Q1507del,
1858	7
1787	12	S1787N,
1786	9	c.5356_5357delCT, L1786R, L1786Q,
1807	14	c.5420dupA,
1861	12	V1861I, V1861F,
1495	10	Y1495S,
1821	15
1798	13	W1798X,
1496	10
1854	5
1825	12	L1825P,
1793	15	M1793K,
1781	13	E1781G, E1781D,
1789	14
1848	15
1499	7
1784	15	E1784X, E1784K,
1498	5	M1498R, M1498T, M1498V,
1839	14	D1839G,
1788	11	c.5361_5364delTGAG,
1500	6	p.K1500del,
1859	10
1876	12
1791	7
1852	10	D1852V,
1792	12	D1792N, D1792V, D1792Y,
1502	5	G1502S, G1502A,
1497	6
1790	11	D1790G, D1790N, p.D1790del,
1494	9
1506	13	P1506S, P1506T,
1503	7	S1503Y,
1840	14