We estimate the penetrance of LQTS for KCNQ1 L250H is 62%.
This variant was found in a total of 8 carriers in 4 papers or gnomAD,
4 had LQTS.
L250H is not present in gnomAD.
L250H has not been functionally characterized.
This residue is located in a Hotspot region for LQT1.
In silico predictions, functional data (if available), and location in structure are equivalent to observing
7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers
lead us to estimate the LQTS penetrance for KCNQ1 L250H around
62% (11/18).
In Silico Data
PROVEAN
PolyPhen-2
BLAST-PSSM
REVEL
Penetrance Density (%)
-6.8
0.997
0
0.958
74
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.
L250H has 30 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.