We estimate the penetrance of LQTS for SCN5A Y1795C around 90% and the Brugada syndrome penetrance around 4%. SCN5A Y1795C was found in a total of 20 carriers in 10 papers and/or in gnomAD: 0 had Brugada syndrome, 20 had LQTS. Y1795C is not present in gnomAD. Y1795C has been functionally characterized in 20 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 (1 diagnosed with Brugada syndrome) and 5 individuals for LQTS (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A Y1795C around 90% (22/30) and the Brugada syndrome penetrance around 4% (1/30).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-8.32	1	-4.28	0.964	11	64

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
11410597	2001	3		3	0	0
15840476	2005	1		1	0	0
18929331	2008	11		8	0	3	AF
24667783	2015	1		1	0	0
22129298	2012	1		1	0	0
25904541	2015	1		1	0	0
27566755	2016	3		3	0	0
16980337	2007	7		7	0	0
19716085	2009	1		1	0	0
30059973	2018	2		2	0	0
LITERATURE, COHORT, AND GNOMAD:	-	20	0	20	0		-
VARIANT FEATURES ALONE:	-	15	12	2	1	-	-

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)
16254012	2006	HEK	100
12814325	2003
15840476	2005
18929331	2008
24667783	2015
14990510	2004
16929919	2006
22129298	2012
25904541	2015
27566755	2016
16520741	2006
16520744	2006	HEK				167
16798729	2006	HEK		0.5	-0.5	514
16980337	2007	HEK				829
19716085	2009
30059973	2018
12796143	2003	HEK
12417563	2002	HEK	120	0	0	167
11410597	2001	HEK	121	-1	-2.8	180
28087622	2017	HEK	98	-5.3	-3.1	276

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
1850	7	C1850S,
1855	14
1803	13
1814	14
1794	4
1849	11	H1849R,
1856	14
1806	12	p.Thr1806SerfsX27,
1853	10	I1853V,
1795	0	p.Y1795_E1796insD, Y1795N, Y1795H, Y1795C,
1818	13
1801	11
1802	10
1820	13	A1820T, A1820V,
1504	6	K1504E,
1851	9	M1851V, M1851I,
1501	10	p.L1501_K1505del, L1501V,
1857	12
1507	6	p.Q1507_P1509del,
1505	8	p.K1505_Q1507del, K1505N,
1858	13
1509	12	P1509T,
1808	12
1787	13	S1787N,
1804	14
1786	13	L1786Q, L1786R, c.5356_5357delCT,
1807	10	c.5420dupA,
1821	11
1798	6	W1798X,
1854	8
1825	11	L1825P,
1797	8	I1797V,
1800	10
1793	8	M1793K,
1789	11
1848	13
1817	10
1796	7
1799	8
1788	10	c.5361_5364delTGAG,
1638	15	R1638Q, R1638X,
1500	11	p.K1500del,
1791	7
1852	12	D1852V,
1792	7	D1792Y, D1792V, D1792N,
1508	11
1502	11	G1502A, G1502S,
1805	10
1497	14
1790	10	D1790N, D1790G, p.D1790del,
1809	12	I1809M,
1506	6	P1506T, P1506S,
1503	10	S1503Y,
1822	12	c.5464_5467delTCTG, c.5464-5467delTCTG,