We estimate the penetrance of LQTS for SCN5A H558R around 0% and the Brugada syndrome penetrance around 0%. SCN5A H558R was found in a total of 62976 carriers in 12 papers and/or in gnomAD: 7 had Brugada syndrome, 1 had LQTS. H558R is present in 62556 alleles in gnomAD. H558R has been functionally characterized in 67 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 H558R around 0% (1/62986) and the Brugada syndrome penetrance around 0% (7/62986).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
3.92	0	2.01	None	1	0

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
12569159	2003	5		0	0	1	AV Block
17227473	2007	2		0	2	0
17544529	2008	1		0	0	1	Sudden death
17675083	2007	1		0	0	1	Arrymthmic story during AMI
19322600	2009	16		0	0	16	SIDS
20123697	2010	3		0	3	0
21216356	2011	2		1	0	1	IVF
21705349	2011	1		0	1	0
23085483	2013	1		0	1	0
20129283	2010	408		0	0	0
29325976	2018	1		0	1	0
29672598	2018	2		0	0	2	SUDS
LITERATURE, COHORT, AND GNOMAD:	-	62976	62968	1	7		-
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)
14500339	2003	HEK	83	-2	1	97
29325976	2018
10807545	2000
11997281	2002
12569154	2003
14985827	2004
14985827	2004
15161528	2004
15851227	2004
15898185	2004
16132053	2005
16632547	2006
16712702	2006
17227473	2007
17534376	2007
17544529	2008
17675083	2007
17993325	2007
19322600	2009
19345130	2009
19549036	2009
20384651	2010		114	-1.7	-1.5
20004937	2010
20123697	2010
21216356	2011
26798387	2016
20403459	2010
21109022	2011
17016421	2006
17185994	2007
17185997	2007
18368697	2008
18452871	2008
18452872	2008
18803136	2008
19056759	2009
19083750	2007
19305639	2009
20137763	2010
20586826	2010
15992732	2005	HEK	97	0	-6
21167004	2010
21705349	2011
21779290	2011
21840964	2011
22117993	2011
22370996	2013
22407026	2012
22835975	2012
24951663	2014
25177937	2014
25871451	2015
26084969	2015
26109178	2015
26401487	2015
27380173	2016
27381756	2016
28336205	2017
15992733	2005
16880338	2006
20451667	2010
23085483	2013	CHO
12454206	2003	HEK
20129283	2010
12569159	2003	HEK	100	-1.4	1.8
29672598	2018
16864729	2006	HEK	82		-2.6

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
543	15	F543L,
544	14
545	14
546	13
547	13
548	12
549	11
550	11
551	10	A551V, A551T,
552	9	G552W, G552R,
553	8	E553K, E553X,
554	8	S554N, S554I,
555	7	E555K,
556	5
557	4	H557Y, H557L, H557Q,
558	0	H558R,
559	4	T559R, T559I,
560	5
561	7
562	8
563	8	V563G,
564	9
565	10
566	11
567	11	L567Q,
568	12	R568C, R568H,
569	13	R569W, c.1705dupC, R569Q,
570	13	T570N,
571	14	S571I,
572	14	A572D, A572F, A572S, A572V,
573	15	Q573E, Q573R, Q573X,