We estimate the penetrance of LQTS for SCN5A R367H around 3% and the Brugada syndrome penetrance around 69%. SCN5A R367H was found in a total of 16 carriers in 18 papers and/or in gnomAD: 13 had Brugada syndrome, 0 had LQTS. R367H is not present in gnomAD. R367H has been functionally characterized in 19 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 (5 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 R367H around 3% (0/26) and the Brugada syndrome penetrance around 69% (18/26).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-4.91	1	-3.14	0.972	71	15

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
15028074	2004	11		0	9	0
14687250	2004	3		0	1	1	atrial standstill
22028457	2011	1		0	0	1	VF
11823453	2002	1		0	0	1	SUNDS
29024690	2017	1		0	1	0
15520322	2004	8		0	6	0
17697823	2007	2		0	2	0
22899775	2012	2		0	0	2	Conduction defects
26173111	2015	1		0	1	0
28341781	2017	1		0	1	0
19251209	2009	1		0	1	0
24529773	2014	1		0	0	1	SUNDS
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
29709101	2018	1		0	1	0
30059973	2018	1		1	0	0
LITERATURE, COHORT, AND GNOMAD:	-	16	3	0	13		-
VARIANT FEATURES ALONE:	-	15	10	0	5	-	-

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)
29024690	2017	hiPSC	55	7.42	-8.51	50
15028074	2004	HEK	0
14687250	2004	HEK-tSA201	0
22028457	2011	HEK-tSA201	0
11823453	2002	Xeno	0
29709101	2018
30059973	2018
15028075	2004
15520322	2004
17697823	2007
22899775	2012
26173111	2015
28341781	2017
19251209	2009
24529773	2014
20129283	2010
20129283	2010
20129283	2010
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
364	5
919	13
901	11	E901K, S901L,
276	13	L276Q, L276P,
363	6
896	15	C896S,
404	15	L404Q, L404V,
348	13	P348A,
360	11
396	11	V396A, V396L,
894	12	I894M,
355	11	F355I, F355C,
372	4
401	12	S401P,
371	8	Q371E,
1711	12	c.5131delG,
928	15	L928P,
361	10
904	9	W904X,
366	7
365	7
1706	13	Q1706H,
376	9	R376H, R376C,
354	11
897	10	G897E, G897R,
927	15	N927S, N927K,
369	9	M369K,
378	12
902	12
402	15	F402L,
349	11	D349N,
373	6
1712	14	G1712S, G1712C,
379	13
898	10
893	13	R893C, R893H,
922	15	V922I,
272	14
397	11	I397V, I397F, I397T,
405	14
362	10
261	12
920	11
1709	13	T1709R, p.T1709del, T1709M,
900	6
392	13
393	11
916	12
264	13
347	14
351	13	G351D, G351V, G351C, G351S,
265	12	A265V,
374	8	W374G,
350	12	H350Q,
358	15
903	9	p.M903CfsX29,
367	0	R367H, R367C, R367L,
359	13	A359T, p.A359PfsX12,
370	7	T370M,
381	12	c.1141-3C>A, c.1140+1G>A,
923	11
905	14
375	10
352	12	Y352C,
368	5
899	6
1710	14	S1710L,
380	12
915	15	C915R,
268	13	G268S,
377	6
400	13	G400E, G400R, G400A,
1419	14	K1419E,
353	9	T353I,
907	13