We estimate the penetrance of LQTS for SCN5A R222Q around 30% and the Brugada syndrome penetrance around 27%. SCN5A R222Q was found in a total of 2 carriers in 11 papers and/or in gnomAD: 1 had Brugada syndrome, 1 had LQTS. R222Q is not present in gnomAD. R222Q has been functionally characterized in 13 papers. This residue is located in a 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 (2 diagnosed with Brugada syndrome) and 5 individuals for LQTS (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A R222Q around 30% (2/12) and the Brugada syndrome penetrance around 27% (3/12).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-3.9	0.995	-0.69	0.984	28	30

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
22710484	2012	2		0	0	2	DCM, conduction disease
22766342	2012	5		0	0	5	DCM
19412328	2008	1		0	0	1	DCM
20458009	2010	6		0	0	6	DCM
21167004	2010	6		0	0	6	DCM
21596231	2011	2		0	0	2	DCM
22999724	2012	7		0	0	7	DCM, ventricular ectopy, conduction abnormalities
19716085	2009	1		1	0	0
20129283	2010	1		0	1	0
29871609	2018	2		0	0	2	DCM
30059973	2018	1		1	0	0
LITERATURE, COHORT, AND GNOMAD:	-	2	0	1	1		-
VARIANT FEATURES ALONE:	-	15	12	1	2	-	-

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)
19412328	2008
20458009	2010
25624448	2015
21167004	2010
21596231	2011
22999724	2012
24815523	2014	tsA201		-13.9	-6.7	69
22766342	2012	COS-7	122	-11.7	-5
19716085	2009
20129283	2010
30059973	2018
29871609	2018
22710484	2012	CHO	110	-9	-7.3

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
223	6	V223L,
856	10	V856L,
859	9
198	14
149	13
147	10
164	9	F164L,
209	14	N209S, N209T,
195	15
228	14	K228R,
227	13	L227P,
171	15
143	13
137	15	I137V,
142	14
156	13	W156R, W156X,
158	12	K158T,
197	13
229	15
163	13	c.486delC,
216	10	S216X, S216L,
851	12	c.2552_2553dupGT, c.2550_2551dupGT, F851L, p.F851CfsX19,
221	8
196	12
169	14
852	11
854	13	c.2559delT,
222	0	R222X, R222Q, R222L,
224	8	L224F,
857	13	G857D,
150	14
157	13	T157I,
160	12	p.V160fs,
226	10	A226V, A226G,
205	12	Y205X, c.612-2A>G,
860	13	p.L860fsx89,
206	10
166	13	A166T,
858	12	M858L,
144	8
217	9
855	9
199	11	S199T,
148	7
165	9
884	15
210	15	I210T,
204	6	c.611+1G>A, c.611+3_611+4dupAA, A204V, A204T,
162	12	Y162H, Y162C,
146	13	V146A, V146M,
203	8
208	10	E208K,
168	10
202	11	I202T,
141	11	I141V, I141N,
167	13
853	15
161	8	E161Q, E161K,
201	9
219	6	R219H, c.656_657insATTCA, R219C, p.R219HfsX11,
225	9	R225W, R225Q,
151	10
218	8
207	8
212	14	L212P, L212Q,
215	13	p.L215CfsX10,
200	7
145	10
140	12
220	7	T220I,