KCNH2 Variant E481K Detail

We estimate the penetrance of LQTS for KCNH2 E481K is 37%. We are unaware of any observations of this variant in individuals. E481K is not present in gnomAD. E481K 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E481K around 37% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.707 0.998 1 0.929 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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 7 3 -
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.

E481K has 49 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
481 0
482 4 V482A,
480 4 E480V,
6 4 G6R,
476 6 V476I,
477 6
478 7 A478D,
7 7
8 7
483 7 V483I,
479 7
9 8 A9V, A9T,
4 8
765 8
475 8 Y475C, Y475Del,
5 9
827 9
699 9 E699D, E699D,
402 10 H402R,
474 10 T474I,
484 10
10 11
764 11
703 11
826 11 T826A, T826I,
702 11
403 12
766 12
488 12 R488C, R488H,
695 12
13 12 T13N,
825 12
3 13
401 13
492 13 H492Y,
767 13 D767X,
706 13 S706F, S706C,
698 13 E698K, E698X,
489 13 I489I, I489F,
824 13
763 14
485 14 H485X,
700 14
473 14 T473P,
696 14 R696C, R696H,
828 14
704 15 A704V, A704T,
11 15 Q11H, Q11H, Q11L,
16 15 D16A,