We estimate the penetrance of LQTS for SCN5A R814Q around
10% and the Brugada syndrome penetrance around
21%. SCN5A R814Q was found in a total of
22 carriers in 6 papers and/or in gnomAD:
5 had Brugada syndrome, 2 had LQTS.
R814Q is present in 7 alleles in gnomAD.
R814Q has been functionally characterized in 7 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 (1 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
R814Q around 10% (2/32)
and the Brugada syndrome penetrance around 21%
(6/32).
In Silico Data
PROVEAN
PolyPhen-2
BLAST-PSSM
REVEL
Penetrance Density BrS (%)
Penetrance Density LQT3 (%)
-3.97
0.999
-2.66
0.967
24
23
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).
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.
Functional Data
Peak and late/persistent current are relative to wildtype (100% being no different from wildtype).
V0.5 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.
R814Q has 70 previously observed neighbors within 15 angstroms
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.