We estimate the penetrance of LQTS for SCN5A G1319V around 2% and the Brugada syndrome penetrance around 31%. SCN5A G1319V was found in a total of 17 carriers in 12 papers and/or in gnomAD: 6 had Brugada syndrome, 0 had LQTS. G1319V is present in 11 alleles in gnomAD. G1319V has been functionally characterized in 13 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 (2 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 G1319V around 2% (0/27) and the Brugada syndrome penetrance around 31% (8/27).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-7.96	1	-5.28	0.967	29	5

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
12106943	2002	1		0	1	0
19843921	2009	1		0	1	0
21273195	2011	3		0	3	0
22885917	2012	2		0	2	0
25179549	2014	2		0	0	2	DCM
17854786	2007	1		0	1	0
19251209	2009	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	3		0	3	0
29325976	2018	1		0	1	0
29759671	2018	1		0	1	0
30059973	2018	8		8	0	0
LITERATURE, COHORT, AND GNOMAD:	-	17	11	0	6		-
VARIANT FEATURES ALONE:	-	15	13	0	2	-	-

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)
12106943	2002
19843921	2009
21273195	2011
22885917	2012
24573164	2014	HEK	75		-1.92
25179549	2014
17854786	2007
19251209	2009
20129283	2010
20129283	2010
29325976	2018
29759671	2018
30059973	2018

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
1328	14	V1328M,
1659	5
1480	10	c.4438-1C>T, c.4437+5G>A,
1773	15
1653	11
1315	8
1771	15	I1771T,
1652	13	M1652R, M1652T,
1314	9	c.3940_3941delCT,
1320	4	M1320I,
1666	15
1656	6
1477	11	K1477N,
1767	13	Y1767C,
1313	11
1660	9	I1660V, I1660S,
1654	12
1769	14
1316	11	R1316L, R1316Q,
1766	12	M1766V, M1766L, M1766T,
1319	0	G1319V,
1774	14	N1774D, c.5321_5324dupACTT,
1479	14
1473	11	F1473C, F1473S,
1663	11
1657	10
1662	10
1324	8
1481	14	G1481V, G1481R, G1481E,
1317	5	F1317C,
1327	12
1318	4
1321	6	R1321K,
1323	6	V1323G,
1770	11	I1770V,
1322	5	c.3963+2T>C, c.3963+4A>G,
1312	12
1326	11	A1326S,
1763	14	V1763L, V1763M,
1311	14	L1311P,
1476	10	Q1476R, Q1476X,
1661	11	G1661E, G1661R,
1655	8
1325	10	N1325S,
1664	14
1658	10