We estimate the penetrance of LQTS for SCN5A R1512W around 2% and the Brugada syndrome penetrance around 18%. SCN5A R1512W was found in a total of 19 carriers in 11 papers and/or in gnomAD: 4 had Brugada syndrome, 0 had LQTS. R1512W is present in 14 alleles in gnomAD. R1512W has been functionally characterized in 14 papers. This residue is located in a Mild_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 (1 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 R1512W around 2% (0/29) and the Brugada syndrome penetrance around 18% (5/29).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-7.37	1	-3.06	0.853	7	8

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
27281089	2016	1		0	0	1	SUNDS
12106943	2002	1		0	1	0
20486126	2010	1		0	1	0
26111534	2015	1		0	1	0	SND, AF, VT
19251209	2009	1		0	1	0
24529773	2014	1		0	0	1	SUNDS
26746457	2016	1		0	0	1	AV node disease
10690282	1999	1		0	1	0
20129283	2010	1		0	0	0
10727653	2000	1		0	1	0
29325976	2018	1		0	1	0
LITERATURE, COHORT, AND GNOMAD:	-	19	15	0	4		-
VARIANT FEATURES ALONE:	-	15	14	0	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)
20129283	2010
10727653	2000	HEK-tSA203		0.9	2.6
29325976	2018
15851227	2004
10727647	2000
12106943	2002
27281089	2016	HEK	69	1.3	-1.5	0
15898185	2004
20486126	2010
26111534	2015
19251209	2009
24529773	2014
26746457	2016
10690282	1999	Xeno		-5.1	-3.8	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
1523	7	D1523N,
1521	9	I1521K, I1521T,
1508	14
1585	12	Y1585C,
1803	11
1527	14	K1527R,
1517	12
1525	11	V1525A, V1525M,
1519	6
1584	15
1515	9	N1515S, c.4542+15G>A,
1800	14
1524	11	I1524T,
1512	0	R1512L, R1512W, R1512Q,
1514	7	L1514M,
1518	8
1509	10	P1509T,
1578	14	c.4732_4733dupAA,
1804	12
1799	13
1526	10	T1526P,
1516	13	L1516sp,
1583	11	R1583H, R1583C,
1580	11
1511	6
1802	15
1513	5
1581	8	A1581S,
1582	10	L1582P,
1579	14	L1579fsX53,
1522	5
1520	9
1577	13
1510	8