We estimate the penetrance of LQTS for KCNQ1 R519H is 3%.
This variant was found in a total of 149 carriers in 6 papers or gnomAD,
2 had LQTS.
R519H is present in 7 alleles in gnomAD.
R519H has been functionally characterized in 1 papers.
This residue is located in a Mild_Hotspot region for LQT1.
In silico predictions, functional data (if available), and location in structure are equivalent to observing
2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers
lead us to estimate the LQTS penetrance for KCNQ1 R519H around
3% (4/159).
In Silico Data
PROVEAN
PolyPhen-2
BLAST-PSSM
REVEL
Penetrance Density (%)
-3.71
1.0
-2
0.876
13
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 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 Homozygously Collected
Peak current is relative to wildtype (100% being no different from wildtype).
V0.5 activation is the voltages at which half of the maximal current is reached during an activation in
units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.)
and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).
R519H has 31 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. NOTE: some residues appear multiple times at
different distances. This results from the fact that the functional KV7.1 channel is a homotetramer and occasionally
the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost
column have been observed in at least one individual in the literature or gnomAD.