We estimate the penetrance of LQTS for SCN5A P2006A around 3% and the Brugada syndrome penetrance around 1%. SCN5A P2006A was found in a total of 266 carriers in 19 papers and/or in gnomAD: 1 had Brugada syndrome, 8 had LQTS. P2006A is present in 252 alleles in gnomAD. P2006A has been functionally characterized in 22 papers. This residue is located in a Non_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 (0 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 P2006A around 3% (8/276) and the Brugada syndrome penetrance around 1% (1/276).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-1.01	0	-1.52	None	3	1

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
17210841	2007	2		0	0	2	SIDS
10961955	2000	1		1	0	0
16379539	2005	1		1	0	0
19412328	2008	1		0	0	1	DCM
19606473	2009	1		0	1	0
20102864	2010	1		0	0	1	SUD
20875080	2011	1		0	0	1	SUDEP
22360817	2012	2		2	0	0
22677073	2012	1		0	0	1	SUDS
23631430	2013	1		1	0	0
23714088	2013	1		1	0	0
24606995	2014	1		1	0	0
25163546	2015	1		0	0	1	DCM
21109022	2011	1		0	0	0
21070882	2011	2		1	0	0
21410720	2011	5		0	0	5	SCD
23571586	2013	2		0	0	2	stillbirth, SUDS
20129283	2010	3		0	0	0
29672598	2018	1		0	0	1	SUDS
LITERATURE, COHORT, AND GNOMAD:	-	266	257	8	1		-
VARIANT FEATURES ALONE:	-	15	15	0	0	-	-

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)
29672598	2018
17210841	2007	tsA203	100	-0.2	4.7	245
10961955	2000
16379539	2005
16712702	2006
19412328	2008
19606473	2009
20102864	2010
20875080	2011
22360817	2012
22677073	2012
23631430	2013
23714088	2013
24606995	2014
25163546	2015
21109022	2011
21070882	2011
21410720	2011
23571586	2013
17646591	2007
21130900	2011
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
1991	15	R1991Q, R1991W,
1992	14	G1992A,
1993	14
1994	13
1995	13	Y1995X,
1996	12	S1996N, S1996R,
1997	11	H1997R,
1998	11
1999	10
2000	9	D2000Y,
2001	8
2002	8	A2002T,
2003	7	D2003N,
2004	5	p.F2004dup, F2004V, F2004I, F2004L,
2005	4	P2005L, P2005S, P2005A,
2006	0	P2006A, p.Pro2006del, P2006T, p.P2006LfsX32,
2007	4	p.S2007FfsX7,
2008	5	P2008L,
2009	7	D2009E,
2010	8	R2010G,
2011	8
2012	9	R2012C, R2012H,
2013	10
2014	11
2015	11
2016	12	V2016M, V2016L,