KCNH2 Variant E480K Detail

We estimate the penetrance of LQTS for KCNH2 E480K is 63%. We are unaware of any observations of this variant in individuals. E480K is not present in gnomAD. E480K 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E480K around 63% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.196 0.989 0 0.927 71
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 4 6 -
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.

E480K has 45 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.

Neighbor Distance (Angstroms) Variants Observed in Individuals
480 0 E480V,
481 4
477 4
479 5
478 5 A478D,
482 5 V482A,
483 7 V483I,
476 7 V476I,
475 8 Y475Del, Y475C,
6 8 G6R,
827 8
9 9 A9T, A9V,
8 10
765 10
488 10 R488C, R488H,
7 10
484 10
826 10 T826A, T826I,
4 10
474 11 T474I,
492 11 H492Y,
10 12
13 12 T13N,
764 12
703 12
489 12 I489I, I489F,
5 12
825 12
402 12 H402R,
699 12 E699D, E699D,
16 13 D16A,
766 13
20 14 R20L, R20G,
485 14 H485X,
17 14
491 14 V491I,
702 14
828 14
706 14 S706C, S706F,
824 14
487 14 G487S, G487R,
763 14
403 15
473 15 T473P,
786 15