We estimate the penetrance of LQTS for SCN5A G752R around 3% and the Brugada syndrome penetrance around 59%. SCN5A G752R was found in a total of 10 carriers in 10 papers and/or in gnomAD: 8 had Brugada syndrome, 0 had LQTS. G752R is present in 1 alleles in gnomAD. G752R 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 (3 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 G752R around 3% (0/20) and the Brugada syndrome penetrance around 59% (11/20).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-7.66	0.981	-3.37	0.974	47	8

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
12693506	2003	6		0	5	0
12106943	2002	1		0	1	0
16643399	2006	1		0	1	0
20031634	2009	6		0	4	0
22885917	2012	2		0	2	0
24365614	2014	1		0	0	1	Aflutter
20022821	2010	2		0	2	0
19251209	2009	1		0	1	0
20129283	2010	1		0	1	0
20129283	2010	1		0	1	0
LITERATURE, COHORT, AND GNOMAD:	-	10	2	0	8		-
VARIANT FEATURES ALONE:	-	15	12	0	3	-	-

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)
19251209	2009
20042374	2010
20129283	2010
20022821	2010
20129283	2010
32533946	2020	HEK	23	22.6
12106943	2002
16643399	2006
20031634	2009
22885917	2012
24365614	2014
12693506	2003	COS	6	30	-10

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
723	14	I723V,
758	10	G758E,
811	10	c.2435_2436+3delTGGTAinsCGCCT, R811G, R811H,
733	6	F733L,
741	14	p.M741_T742delinsI ,
808	13	R808H, R808C, R808P,
745	11
746	12	E746K,
760	11	p.F760SfsX5,
759	10	I759V, p.I759FfsX6, c.2274delG,
792	12
755	5
731	11	T731I,
800	15	R800H, R800C, R800L,
754	5
726	10
737	12
750	6	Q750R,
749	6
743	14
793	14	L793F,
728	13	V728I,
762	15
747	9	E747A,
727	12
735	13	A735E, A735T, A735V,
732	11
734	10	M734V, c.2201dupT,
756	5
814	11	R814Q,
757	8
761	13
744	14
752	0	G752R,
725	14
751	4	V751F, V751I,
796	11
736	12	L736P,
730	7	N730K,
789	15	V789I, V789A,
753	4
729	9	p.L729del,
795	13
748	7	M748I,
799	14