We estimate the penetrance of LQTS for KCNH2 R534C is 54%.
This variant was found in a total of 24 carriers in 14 papers or gnomAD (version 4),
20 had LQTS.
R534C is present in 2 alleles in gnomAD.
We have tested the trafficking efficiency of this variant, 0% of WT
with a standard error of 0%; in our analysis we used SE < 20% as 'high quality'.
Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong.
R534C has been functionally characterized in 3 papers.
This residue is located in a Hotspot region for LQT2.
In silico predictions, functional data (if available), and location in structure are equivalent to observing
2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers
lead us to estimate the LQTS penetrance for KCNQ1 R534C around
54% (22/34).
In Silico Data
PROVEAN
PolyPhen-2
BLAST-PSSM
REVEL
Penetrance Density (%)
-7.668
1.0
-4
0.954
81
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
Steady state (S.S.) and peak tail 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. Recovery from inactivation (Rec. inact.)
and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).
R534C has 59 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 since the functional KV11.1 channel (protein product of KCNH2/hERG) 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.