We estimate the penetrance of LQTS for SCN5A E1784K around 69% and the Brugada syndrome penetrance around 19%. SCN5A E1784K was found in a total of 164 carriers in 40 papers and/or in gnomAD: 31 had Brugada syndrome, 114 had LQTS. E1784K is not present in gnomAD. E1784K has been functionally characterized in 51 papers. This residue is located in a Mild_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 E1784K around 69% (116/174) and the Brugada syndrome penetrance around 19% (32/174).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-3.57	0.82	0.04	0.91	20	61

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
24439875	2014	4		1	2	1	Sino-atrial block
18451998	2008	50		38	9	0
27381756	2016	17		10	7	0
10961955	2000	3		3	0	0
10973849	2000	1		1	0	0
11901046	2002	1		0	1	0
12877697	2003	3		3	0	0
15840476	2005	4		4	0	0
16379539	2005	2		2	0	0
17971661	2008	8		5	2	0
18452873	2008	2		1	0	1	AF
18508782	2008	10		0	9	1	SD
19181867	2009	1		0	1	0
20123697	2010	1		0	1	0
20541041	2010	8		8	0	0
20566482	2010	1		0	1	0
20659946	2010	4		4	0	0
21321465	2011	1		0	1	0
22360817	2012	13		13	0	0
23098067	2012	1		1	0	0
23631430	2013	1		1	0	0
24667783	2015	1		1	0	0
24762805	2014	4		4	0	0	BrS (overlap), SSS
26669661	2016	34		20	0	0
26729854	2016	1		0	1	0
26921764	2016	9		0	9	0
26940925	2016	1		1	0	0
28341781	2017	2		0	2	0
28781849	2017	2		0	1	0
24871449	2014	14		14	0	0
25904541	2015	3		3	0	0
27566755	2016	70		70	0	0
27915266	2017	16		16	0	0
27677334	2016	1		1	0	0
10377081	1999	4		4	0	0
19716085	2009	15		15	0	0
20129283	2010	14		0	14	0
10727653	2000	1		1	0	0
29325976	2018	4		0	4	0
30059973	2018	69		69	0	0
LITERATURE, COHORT, AND GNOMAD:	-	164	19	114	31		-
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)
29325976	2018
30059973	2018
26131924	2015	CHO	106	-0.16	-16.19	405
24439875	2014	tsA201	39	0	-18.4	1436
10727653	2000	HEK-tSA201		8.8	-14.4	500
32533946	2020	HEK	52		-5.4
20129285	2010
18451998	2008	tsA201	60	12.5	-15	348
29483621	2018	HEK	144	5.32	-11.84	50
10727647	2000
10961955	2000
10973849	2000
11901046	2002
12877697	2003
15840476	2005
27381756	2016	tsA201	70		-11.03	0
16379539	2005
17971661	2008
18452873	2008
19181867	2009
20123697	2010
20541041	2010
20566482	2010
18508782	2008
20659946	2010
21321465	2011
22360817	2012
23098067	2012
23631430	2013
24667783	2015
24762805	2014
26669661	2016
26729854	2016
26921764	2016
26940925	2016
28341781	2017
28781849	2017
29017927	2017
24871449	2014
24920323	2014
25904541	2015
27566755	2016
27915266	2017
28412158	2017
20188230	2010
28734073	2017	HEK
27677334	2016	hiPSC
28898267	2017	Oocytes
10377081	1999	Xeno		NA	-12.1	1000
19716085	2009
20129283	2010

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
1785	4
1778	12
1866	8
1824	11	P1824A,
1777	12	V1777L, V1777M,
1492	11
1491	11	Q1491H,
1863	9
1501	15	L1501V, p.L1501_K1505del,
1860	14	c.5577_5578dupAA,
1874	14
1862	6
1779	11	T1779M,
1493	6	p.K1493del, K1493R, K1493X,
1867	11
1858	11
1865	6
1776	14
1787	11	S1787N,
1786	8	c.5356_5357delCT, L1786R, L1786Q,
1861	9	V1861I, V1861F,
1495	14	Y1495S,
1864	11
1496	11
1870	15	A1870T,
1825	14	L1825P,
1781	8	E1781D, E1781G,
1488	12	T1488R,
1784	0	E1784X, E1784K,
1498	13	M1498R, M1498T, M1498V,
1780	8	E1780G,
1500	13	p.K1500del,
1859	12
1869	13
1791	14
1868	8
1823	15	p.E1823HfsX10, E1823K,
1783	5
1497	10
1490	7
1790	13	D1790G, D1790N, p.D1790del,
1494	9
1489	11	E1489D,
1782	8