We estimate the penetrance of LQTS for SCN5A D1790G around 80% and the Brugada syndrome penetrance around 4%. SCN5A D1790G was found in a total of 45 carriers in 12 papers and/or in gnomAD: 1 had Brugada syndrome, 38 had LQTS. D1790G is not present in gnomAD. D1790G has been functionally characterized in 22 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 D1790G around 80% (40/55) and the Brugada syndrome penetrance around 4% (2/55).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-6.47	1	-4.39	0.992	2	56

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
10627139	1998	26		23	0	0
10973849	2000	1		1	0	0
16414944	2005	1		1	0	0
19140927	2009	1		1	0	0
20102920	2010	35		35	0	0
22360817	2012	2		2	0	0
26304620	2015	2		0	1	0
26669661	2016	14		12	0	0
27566755	2016	30		30	0	0
28339995	2017	85		85	0	0
27733495	2016	8		8	0	0
30059973	2018	7		7	0	0
LITERATURE, COHORT, AND GNOMAD:	-	45	6	38	1		-
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)
9686753	1998	HEK	83	0	-16.3
30059973	2018
10920073	2000	HEK		7	-15
11150514	2000	HEK	100	5.36	-14.64	2000
12401812	2003
10627139	1998
10758053	2000
10973849	2000
12814325	2003
16414944	2005
19140927	2009
20102920	2010
22360817	2012
28087622	2017	HEK	81	5.12	-14.8	121
26304620	2015
26669661	2016
29017927	2017
27566755	2016
28339995	2017
10952963	2000	HEK			-15.6
25370050	2014	HEK		3.9	-13.5
27733495	2016	tsA201

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	15	C1850S,
1855	15
1785	9
1794	8
1856	14
1778	12
1853	14	I1853V,
1795	10	Y1795H, p.Y1795_E1796insD, Y1795N, Y1795C,
1818	13
1652	15	M1652R, M1652T,
1777	15	V1777L, V1777M,
1824	7	P1824A,
1820	12	A1820V, A1820T,
1504	11	K1504E,
1641	9
1501	11	L1501V, p.L1501_K1505del,
1860	14	c.5577_5578dupAA,
1857	12
1862	13
1639	13	G1639A,
1779	14	T1779M,
1493	14	p.K1493del, K1493R, K1493X,
1858	10
1865	14
1787	4	S1787N,
1786	5	c.5356_5357delCT, L1786R, L1786Q,
1648	11
1861	10	V1861I, V1861F,
1649	14	A1649V,
1864	14
1821	9
1644	10	R1644L, R1644C, R1644H,
1640	14
1798	14	W1798X,
1826	11	R1826C, R1826H,
1496	13
1854	11
1825	7	L1825P,
1797	11	I1797V,
1793	6	M1793K,
1781	10	E1781D, E1781G,
1789	4
1817	13
1645	10	T1645M,
1784	13	E1784X, E1784K,
1827	14
1498	14	M1498R, M1498T, M1498V,
1796	10
1780	15	E1780G,
1788	7	c.5361_5364delTGAG,
1638	11	R1638Q, R1638X,
1500	9	p.K1500del,
1791	5
1637	14
1792	7	D1792N, D1792Y, D1792V,
1823	9	p.E1823HfsX10, E1823K,
1502	15	G1502A, G1502S,
1783	12
1642	13	G1642E,
1497	11
1790	0	D1790G, D1790N, p.D1790del,
1647	15
1503	14	S1503Y,
1822	7	c.5464-5467delTCTG, c.5464_5467delTCTG,
1646	15
1782	10