We estimate the penetrance of LQTS for SCN5A G1408R around 4% and the Brugada syndrome penetrance around 33%. SCN5A G1408R was found in a total of 28 carriers in 13 papers and/or in gnomAD: 8 had Brugada syndrome, 1 had LQTS. G1408R is not present in gnomAD. G1408R has been functionally characterized in 18 papers. This residue is located in a 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 (4 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 G1408R around 4% (1/38) and the Brugada syndrome penetrance around 33% (12/38).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-7.79	1	-4.96	0.98	56	3

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
14523039	2003	13		0	0	3	SSS
16643399	2006	1		0	1	0
20031634	2009	13		0	4	0
20541041	2010	1		1	0	0
26921764	2016	1		0	1	0
26941339	2016	1		0	1	0
28341781	2017	1		0	1	0
19251209	2009	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	2		0	2	0
29574140	2018	1		0	1	0
30059973	2018	2		2	0	0
LITERATURE, COHORT, AND GNOMAD:	-	28	19	1	8		-
VARIANT FEATURES ALONE:	-	15	11	0	4	-	-

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)
19251209	2009
20129284	2010
20129285	2010
20188230	2010
20129283	2010
20129283	2010
20129283	2010
29574140	2018
30059973	2018
20384651	2010		0
14523039	2003	HEK-tSA201	0
16643399	2006
20031634	2009
20541041	2010
26921764	2016
26941339	2016
28341781	2017
20539757	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
1355	12
1403	8
1357	10	A1357V,
1417	13
1352	8
1406	5	G1406R, G1406E,
1457	14
1453	11
1351	11	M1351V, M1351R,
739	13
1397	13	c.4190delA, c.4189delT,
1449	11	Y1449C, Y1449S,
1350	9	I1350T, I1350L,
1723	13	T1723N,
1344	14	F1344S, F1344L,
1450	12
1398	12	V1398M,
1411	5
1353	8	V1353M,
1407	3
737	12
1410	5
1714	13	D1714G,
1358	12	G1358W, G1358R,
1348	10	F1348L,
1404	6
1423	15	D1423H,
1721	14
1349	6
1753	14	T1753A,
1346	9	L1346P, L1346I,
1359	13	K1359M, K1359N,
1341	14
1356	9	c.4066_4068delTT,
1412	5	L1412F,
1408	0	G1408R,
735	11	A735V, A735E, A735T,
1420	13	G1420R, G1420V, G1420P, G1420D,
1360	11	F1360C,
734	14	M734V, c.2201dupT,
1401	6
1425	14
1399	12
1454	15
1354	12
1427	13	A1427E, A1427S,
1424	10	I1424V,
738	12
1405	6	V1405M, V1405L,
1409	6	Y1409X, Y1409C,
1400	8	V1400I,
1421	14
1718	15	S1718R,
1343	14
1345	10	W1345C,
1717	14	L1717P,
1342	12
1416	12	c.4245+1G>C, c.4245+2T>A, A1416E, A1416G, c.4245+1G>A,
736	13	L736P,
1749	12	I1749N,
1347	12
1415	10
1428	13	A1428V, A1428S,
1414	9	Q1414H,
1402	5
1413	8