We estimate the penetrance of LQTS for SCN5A F2004L around 9% and the Brugada syndrome penetrance around 22%. SCN5A F2004L was found in a total of 20 carriers in 14 papers and/or in gnomAD: 5 had Brugada syndrome, 2 had LQTS. F2004L is present in 2 alleles in gnomAD. F2004L has been functionally characterized in 18 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 F2004L around 9% (2/30) and the Brugada syndrome penetrance around 22% (6/30).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-0.63	0	-0.21	0.29	23	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
18456723	2008	5		0	1	0
17210841	2007	3		0	0	3	SIDS
16643399	2006	1		0	1	0
22677073	2012	1		0	0	1	SUDS
23714088	2013	1		1	0	0
23936059	2013	1		1	0	0
25163546	2015	1		0	0	1	DCM
21126620	2010	1		0	1	0
23571586	2013	1		0	0	1	stillbirth, SUDS
22685113	2012	1		0	0	1	AF
18071069	2008	1		0	0	1	SCD
20129283	2010	7		0	0	0
29672598	2018	1		0	0	1	SUDS
29672598	2018	2		0	2	1	SUDS
LITERATURE, COHORT, AND GNOMAD:	-	20	13	2	5		-
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)
25163546	2015
29017927	2017
21126620	2010
23465283	2013
23571586	2013
17646591	2007
22685113	2012	HEK
18071069	2008	Xeno
20129283	2010
17210841	2007	tsA202	120	0.7	4.7	386
22677073	2012
29672598	2018
29672598	2018
16643399	2006
18456723	2008	CHO	57
23414114	2013
23714088	2013
23936059	2013

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
1989	15
1990	14	V1990L,
1991	14	R1991Q, R1991W,
1992	13	G1992A,
1993	13
1994	12
1995	11	Y1995X,
1996	11	S1996R, S1996N,
1997	10	H1997R,
1998	9
1999	8
2000	8	D2000Y,
2001	7
2002	5	A2002T,
2003	4	D2003N,
2004	0	p.F2004dup, F2004I, F2004V, F2004L,
2005	4	P2005L, P2005A, P2005S,
2006	5	P2006A, P2006T, p.Pro2006del, p.P2006LfsX32,
2007	7	p.S2007FfsX7,
2008	8	P2008L,
2009	8	D2009E,
2010	9	R2010G,
2011	10
2012	11	R2012C, R2012H,
2013	11
2014	12
2015	13
2016	13	V2016M, V2016L,