We estimate the penetrance of LQTS for SCN5A R1193Q around 1% and the Brugada syndrome penetrance around 1%. SCN5A R1193Q was found in a total of 1486 carriers in 31 papers and/or in gnomAD: 18 had Brugada syndrome, 11 had LQTS. R1193Q is present in 1414 alleles in gnomAD. R1193Q has been functionally characterized in 47 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Mild_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 R1193Q around 1% (11/1496) and the Brugada syndrome penetrance around 1% (18/1496).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-0.46	0.001	0.69	None	2	11

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
11823453	2002	2		0	1	1	SUNDS, SIDS
15121794	2004	1		0	1	0
14967853	2004	1		0	1	0
15851440	2005	3		0	1	1
17227473	2007	1		0	1	0
17905336	2007	3		1	2	0
18976777	2009	1		0	1	0
20123697	2010	4		0	4	0
21273195	2011	1		0	1	0
21321465	2011	2		0	2	0
22677073	2012	1		0	0	1	SUDS
22682427	2012	1		0	0	1	SUDS
23853484	2013	4		0	0	4	VF, SCA
24687331	2014	1		1	0	0
25051102	2014	2		0	0	1	VF
26154754	2015	1		0	1	0
26496715	2016	1		1	0	0
26921764	2016	3		0	3	0
27681629	2016	11		0	0	0
28878402	2017	8		0	0	4	AV block
18245395	2008	7		2	0	5	PCCD
21126620	2010	1		0	1	0
22519808	2012	3		1	0	1	DCM
23105938	2012	29		0	0	16	atrioventricular conduction block
23571586	2013	2		0	0	2	stillbirth, SUDS
24596401	2014	1		0	0	1
26746457	2016	7		4	0	3	AF, BB, AV node disease
16568155	2006	3		1	2	0
25757662	2015	1		0	0	1	SIDS
20129283	2010	12		0	0	0
29672598	2018	2		0	0	2	SUDS
LITERATURE, COHORT, AND GNOMAD:	-	1486	1457	11	18		-
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)
15992732	2005	HEK	101	-1	-2
11823453	2002	Xeno	84		3.9
28584071	2017
26131924	2015	CHO	44	-6.69	2.34	103
30419068	2018	HEK	92	0	0
29672598	2018
14967853	2004
15851227	2004
15851440	2005
15898185	2004
16707561	2006
17227473	2007
17905336	2007
18976777	2009
20123697	2010
21273195	2011
21321465	2011
22677073	2012
22682427	2012
15121794	2004	HEK	100	0	-6	416
23853484	2013
24687331	2014
25051102	2014
26154754	2015
26255078	2016
26496715	2016
26921764	2016
27681629	2016
28878402	2017
16244303	2005
15689442	2005
18245395	2008
20137763	2010
21126620	2010
22407026	2012
22519808	2012
23105938	2012
23571586	2013
24524602	2013
24596401	2014
26746457	2016
28493952	2017
28638671	2017
15992733	2005
16568155	2006	tsA201		2	-5.2
25757662	2015	HEK
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
1178	15	C1178Y,
1179	14
1180	14	A1180V,
1181	13	V1181M, V1181A, V1181L,
1182	13
1183	12	T1183I,
1184	11
1185	11	c.3553_3554delCA,
1186	10	A1186T,
1187	9	P1187Q,
1188	8
1189	8	K1189T,
1190	7	V1190F,
1191	5	W1191X,
1192	4	W1192X,
1193	0	R1193W, R1193Q,
1194	4	L1194M,
1195	5	R1195H, R1195S,
1196	7
1197	8
1198	8
1199	9	Y1199S,
1200	10	H1200R, H1200Y, p.H1200PfsX41,
1201	11	I1201M,
1202	11	V1202M,
1203	12
1204	13
1205	13
1206	14
1207	14
1208	15	E1208X, E1208K,