We estimate the penetrance of LQTS for SCN5A N406K around 69% and the Brugada syndrome penetrance around 15%. SCN5A N406K was found in a total of 5 carriers in 10 papers and/or in gnomAD: 0 had Brugada syndrome, 5 had LQTS. N406K is not present in gnomAD. N406K has been functionally characterized in 13 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a 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 N406K around 69% (6/15) and the Brugada syndrome penetrance around 15% (2/15).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-5.89	1	-5.43	0.832	20	50

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
24112685	2014	1		1	0	0
29983085	2018	1		1	0	0
15840476	2005	1		1	0	0
19996378	2010	1		1	0	0
20541041	2010	1		1	0	0
22360817	2012	2		2	0	0
23631430	2013	1		1	0	0
27566755	2016	1		1	0	0
19716085	2009	1		1	0	0
30059973	2018	2		2	0	0
LITERATURE, COHORT, AND GNOMAD:	-	5	0	5	0		-
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)
20541041	2010
22360817	2012
23631430	2013
24117196	2014
25254341	2014
27566755	2016
19716085	2009
29983085	2018	HEK	31	-3	-3
30059973	2018
16885209	2006	HEK	40
24112685	2014	CHO	21	8.6	2.9	550
15840476	2005
19996378	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
403	7
414	13	M414V,
939	14	L939F,
404	7	L404Q, L404V,
1773	11
1765	9
396	14	V396A, V396L,
1653	11
254	14
1771	6	I1771T,
401	7	S401P,
1652	14	M1652T, M1652R,
1764	10	c.5290delG, V1764F,
371	11	Q371E,
250	12
409	5	L409V, L409P,
928	10	L928P,
1650	10	L1650F,
260	14
366	14
1656	14
933	14
246	14
935	10	L935P,
412	10	V412D,
924	14	V924I,
1762	15	I1762M, p.I1762del,
1470	11
927	12	N927K, N927S,
1466	10	c.4396_4397insG,
1776	13
369	10	M369K,
1767	8	Y1767C,
1660	13	I1660S, I1660V,
1654	13
1769	8
402	7	F402L,
1766	12	M1766V, M1766L, M1766T,
415	15	A415T,
1649	12	A1649V,
1768	5	I1768V,
1774	12	N1774D, c.5321_5324dupACTT,
1473	14	F1473C, F1473S,
256	13
399	12
397	12	I397F, I397V, I397T,
405	4
1657	11
1709	14	T1709R, p.T1709del, T1709M,
930	15	c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1772	7	L1772V,
410	7	A410V,
1770	9	I1770V,
929	13
413	11	A413T, A413E,
408	7
253	12
407	6
936	13
1763	13	V1763M, V1763L,
1760	14
1467	13
1775	10	p.F1775LfsX15, F1775V,
370	12	T370M,
923	15
1469	13	I1469V,
406	0	N406K, N406S,
368	15
411	10	V411M,
932	9
398	11
1647	14
257	12
400	9	G400R, G400E, G400A,
931	13
1646	12
1463	13	N1463Y,