We estimate the penetrance of LQTS for KCNH2 A504V is 22%.
This variant was found in a total of 2 carriers in 1 papers or gnomAD (version 4),
1 had LQTS.
A504V is not present 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.
A504V has not been functionally characterized.
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 A504V around
22% (3/12).
In Silico Data
PROVEAN
PolyPhen-2
BLAST-PSSM
REVEL
Penetrance Density (%)
-3.74
0.992
0
0.92
49
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).
Reported Carrier Data
PubMed ID
Year
Carriers
Unaffected
LQT2
Other Disease
Japan Cohort
2020
2
1
1
LITERATURE, COHORT, AND GNOMAD:
-
2
1
1
-
VARIANT FEATURES ALONE:
-
10
8
2
-
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.
A504V has 51 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.