We estimate the penetrance of LQTS for SCN5A V411M around 83% and the Brugada syndrome penetrance around 5%. SCN5A V411M was found in a total of 18 carriers in 19 papers and/or in gnomAD: 0 had Brugada syndrome, 17 had LQTS. V411M is not present in gnomAD. V411M has been functionally characterized in 21 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 V411M around 83% (19/28) and the Brugada syndrome penetrance around 5% (1/28).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-2.94	1	-1.73	0.947	13	63

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
21193062	2011	1		1	0	0
10961955	2000	1		1	0	0
15840476	2005	1		1	0	0
16712702	2006	1		1	0	0
20541041	2010	1		1	0	0
22360817	2012	1		1	0	0
22885918	2012	1		1	0	0
23098067	2012	4		4	0	0
23631430	2013	1		1	0	0
24606995	2014	1		1	0	0
26496715	2016	2		2	0	0
26498160	2016	1		0	0	1	SD
26669661	2016	6		5	0	0
26940925	2016	1		1	0	0
27485560	2016	1		1	0	0
22721569	2012	1		1	0	0
27566755	2016	7		7	0	0
19716085	2009	3		3	0	0
30059973	2018	10		10	0	0
LITERATURE, COHORT, AND GNOMAD:	-	18	1	17	0		-
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)
30059973	2018
10961955	2000
15840476	2005
16712702	2006
20541041	2010
22360817	2012
22885918	2012
23098067	2012
23631430	2013
24606995	2014
26496715	2016
26498160	2016
26669661	2016
26940925	2016
27485560	2016
29017927	2017
22721569	2012
26888838	2015
27566755	2016
19716085	2009
21193062	2011	HEK	100	-8.1	-7.9	176

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
403	14
414	5	M414V,
939	13	L939F,
1643	12	I1643L,
404	11	L404V, L404Q,
937	15
1778	12
1773	13
249	6	K249X,
247	9	V247L,
254	11
1771	11	I1771T,
1777	13	V1777L, V1777M,
418	10	E418K,
926	14
250	6
409	7	L409V, L409P,
928	10	L928P,
925	14	I925F,
1650	13	L1650F,
417	11
933	10
246	6
935	12	L935P,
1779	10	T1779M,
412	4	V412D,
924	13	V924I,
1470	15
927	14	N927S, N927K,
245	9	Q245K,
1776	10
244	12
1769	14
415	6	A415T,
1649	13	A1649V,
1768	13	I1768V,
1774	13	N1774D, c.5321_5324dupACTT,
256	13
405	11
248	11
241	13
420	14
419	13	Q419X,
930	13	c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
255	14
1772	9	L1772V,
1645	12	T1645M,
239	14	I239V, I239V ,
251	10
410	4	A410V,
1780	13	E1780G,
242	10	A242D,
929	9
416	11	Y416C,
413	6	A413E, A413T,
408	6
253	8
407	6
936	11
1775	7	p.F1775LfsX15, F1775V,
1642	11	G1642E,
406	10	N406K, N406S,
252	11
411	0	V411M,
243	11
932	9
1647	13
257	13
931	14
1646	9
1782	14