We estimate the penetrance of LQTS for SCN5A F103L around 21% and the Brugada syndrome penetrance around 32%. SCN5A F103L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. F103L is not present in gnomAD. F103L has been functionally characterized in 0 papers. This residue is located in a 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 (3 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 F103L around 21% (1/10) and the Brugada syndrome penetrance around 32% (3/10).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
NA	NA	NA	0.942	43	25

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
LITERATURE, COHORT, AND GNOMAD:	-	0	0	0	0		-
VARIANT FEATURES ALONE:	-	15	11	1	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.

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
88	15	S88G,
89	14
90	14	p.Q90WfsX14,
91	13
92	13	T92I, c.274-24C>T,
93	12	F93S,
94	11	I94S, I94V,
95	11	V95I, V95L,
96	10
97	9
98	8
99	8
100	7
101	5	T101I,
102	4
103	0
104	4	R104Q, R104G, R104W,
105	5
106	7	S106T,
107	8
108	8
109	9	N109K,
110	10	A110T,
111	11
112	11	Y112C,
113	12	V113I, V113A,
114	13
115	13	S115G,
116	14
117	14
118	15