We estimate the penetrance of LQTS for SCN5A A572D around 0% and the Brugada syndrome penetrance around 0%. SCN5A A572D was found in a total of 1465 carriers in 12 papers and/or in gnomAD: 1 had Brugada syndrome, 5 had LQTS. A572D is present in 1451 alleles in gnomAD. A572D has been functionally characterized in 16 papers. This residue is located in a Non_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 (0 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 A572D around 0% (5/1475) and the Brugada syndrome penetrance around 0% (1/1475).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-0.35	0.055	-0.16	None	3	4

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
18071069	2008	1		0	0	1	SCD
27287068	2016	1		0	0	1	atrial tachycardia
12820704	2003	3		1	0	0
15840476	2005	3		3	0	0
17161064	2006	1		1	0	0
19412328	2008	1		0	0	1	DCM
20875080	2011	1		0	0	1	SUDEP
22818067	2012	3		0	0	2	AF
25163546	2015	1		0	0	1	DCM
26820365	2016	1		0	0	1	PCCD
28781330	2017	6		0	1	0
29672598	2018	1		0	0	1	SUDS
LITERATURE, COHORT, AND GNOMAD:	-	1465	1459	5	1		-
VARIANT FEATURES ALONE:	-	15	15	0	0	-	-

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)
20875080	2011
22818067	2012
25163546	2015
26820365	2016
28781330	2017
20403459	2010
27243970	2016
20451667	2010
17161064	2006
29672598	2018
27287068	2016	Oocytes	155
19412328	2008
12820704	2003
15840476	2005
23008441	2012	HEK	100		-15
18071069	2008	Xeno	100	-2.5	0.8

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
557	15	H557Q, H557L, H557Y,
558	14	H558R,
559	14	T559I, T559R,
560	13
561	13
562	12
563	11	V563G,
564	11
565	10
566	9
567	8	L567Q,
568	8	R568C, R568H,
569	7	R569W, c.1705dupC, R569Q,
570	5	T570N,
571	4	S571I,
572	0	A572F, A572D, A572S, A572V,
573	4	Q573E, Q573R, Q573X,
574	5	G574E, c.1721delG,
575	7
576	8
577	8	S577N,
578	9	P578T, P578R,
579	10	G579R,
580	11
581	11	S581L,
582	12
583	13	P583L,
584	13	G584R,
585	14
586	14	p.586_587delAL, A586T, A586G,
587	15