We estimate the penetrance of LQTS for SCN5A R1623Q around 78% and the Brugada syndrome penetrance around 8%. SCN5A R1623Q was found in a total of 16 carriers in 19 papers and/or in gnomAD: 0 had Brugada syndrome, 15 had LQTS. R1623Q is not present in gnomAD. R1623Q has been functionally characterized in 26 papers. This residue is located in a Mild_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 (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 R1623Q around 78% (16/26) and the Brugada syndrome penetrance around 8% (2/26).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-3.57	0.485	-0.29	0.95	29	39

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
10200053	1998	1		1	0	0
10973849	2000	1		1	0	0
12574983	2003	1		1	0	0
15051636	2004	1		1	0	0
15184283	2004	2		1	0	0
19863579	2010	1		1	0	0
19996378	2010	1		1	0	0
22360817	2012	2		2	0	0
23631430	2013	1		1	0	0
23995044	2013	4		4	0	0
24218437	2013	1		1	0	0
26498160	2016	1		0	0	1	SD
26940925	2016	1		1	0	0
16922724	2006	1		1	0	0
27539165	2016	1		1	0	0
27566755	2016	1		1	0	0
19716085	2009	3		3	0	0
20129283	2010	1		0	1	0
30059973	2018	6		6	0	0
LITERATURE, COHORT, AND GNOMAD:	-	16	1	15	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)
9495298	1998	CHO	45	NA	NA
10200053	1998
10973849	2000
12574983	2003
15051636	2004
15184283	2004
15210606	2004
19863579	2010
19996378	2010
22360817	2012
23631430	2013
23995044	2013
24218437	2013
26498160	2016
26940925	2016
20090423	2010
29017927	2017
16922724	2006
19167409	2009
27539165	2016
27566755	2016
9506831	1998			0	-1.4
19716085	2009
20129283	2010
30059973	2018
10772658	2000	HEK-tSA201	100		-7.2

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
271	7	L271V,
266	9	L266H,
1544	12	T1544P,
270	5	Q270K,
1627	7
1567	14	F1567L,
1624	6	V1624I,
355	13	F355I, F355C,
1549	14
1538	14
1568	14
356	15	D356N,
1543	14	V1543L, V1543A,
1602	12
1542	11
1601	11	L1601H,
1557	14	I1557V,
1613	14	Q1613H, Q1613L,
1564	11
1599	14
1546	12	M1546T,
1545	7
1630	14	I1630R, I1630V,
1626	6	R1626P, R1626C, R1626L, R1626H,
267	8
1550	14
1625	8
1606	14	T1606I,
1560	12	L1560F,
262	15	S262G,
272	11
274	14	G274C,
273	10
1628	11
1597	13	V1597M,
392	13
389	13	Y389H, Y389X,
269	9
1620	5	T1620M, T1620K,
1565	15	L1565M,
275	13	N275K,
1594	15	F1594S,
264	13
1548	10	E1548K, G1548K,
265	12	A265V,
1619	5	P1619L, P1619Q, c.4856delC,
358	14
263	12	V263I,
1629	13	R1629X, R1629G, R1629Q,
1605	12	c.4813+3_4813+6dupGGGT, G1605C, c.4813+5insTGGG, c.4813+2_4813+5dupTGGG, G1605D,
1547	13	V1547L,
1563	14
1541	11
1617	10	p.F1617del,
268	10	G268S,
1604	14	c.4810+3_4810+6dupGGGT, V1604M,
1622	6
1618	8
1621	7
1598	11	V1598A,
1561	13
1623	0	c.4867delC, R1623X, R1623L, R1623Q,