We estimate the penetrance of LQTS for SCN5A A735V around 1% and the Brugada syndrome penetrance around 52%. SCN5A A735V was found in a total of 8 carriers in 12 papers and/or in gnomAD: 5 had Brugada syndrome, 0 had LQTS. A735V is present in 1 alleles in gnomAD. A735V has been functionally characterized in 12 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 A735V around 1% (0/18) and the Brugada syndrome penetrance around 52% (9/18).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-3.77	0.049	-3.34	0.943	72	10

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	4		0	3	1	SUNDS
17697823	2007	1		0	1	0
22795782	2012	1		0	0	1	Conduction defects
26921764	2016	1		0	1	0
28341781	2017	1		0	1	0
28491738	2016	3		0	1	0
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
29325976	2018	2		0	2	0
30059973	2018	1		1	0	0
LITERATURE, COHORT, AND GNOMAD:	-	8	3	0	5		-
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)
20129283	2010
20129283	2010
11823453	2002	Xeno	100	6.7	-0.1
20129283	2010
30059973	2018
29325976	2018
17697823	2007
22795782	2012
26921764	2016
28341781	2017
28491738	2016
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
1355	15
1403	12
1357	12	A1357V,
742	14	T742A,
811	12	R811G, R811H, c.2435_2436+3delTGGTAinsCGCCT,
733	7	F733L,
741	12	p.M741_T742delinsI ,
808	13	R808H, R808P, R808C,
745	11
1352	11
1406	10	G1406E, G1406R,
746	14	E746K,
1351	12	M1351R, M1351V,
739	14
812	11	L812Q,
1350	6	I1350T, I1350L,
731	6	T731I,
726	15
818	14
1353	8	V1353M,
1407	12
737	6
1410	15
1348	13	F1348L,
1404	9
750	14	Q750R,
1349	8
749	9
1346	8	L1346I, L1346P,
728	10	V728I,
1412	15	L1412F,
727	13
1408	11	G1408R,
735	0	A735E, A735T, A735V,
732	5
734	5	M734V, c.2201dupT,
756	14
814	13	R814Q,
1401	15
1354	10
738	10
752	13	G752R,
1405	6	V1405L, V1405M,
809	14
740	14	p.N740del,
1409	12	Y1409X, Y1409C,
815	11
1343	12
1345	14	W1345C,
1342	12
736	4	L736P,
730	9	N730K,
753	12
1347	11
729	10	p.L729del,
748	12	M748I,
1402	13