KCNH2 Variant E698D Detail

We estimate the penetrance of LQTS for KCNH2 E698D is 7%. We are unaware of any observations of this variant in individuals. E698D is not present in gnomAD. E698D has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E698D around 7% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.799 0.999 1 0.848 3
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 10 0 -
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.

E698D has 61 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
698 0 E698X, E698K,
697 5 L697X,
694 5 R694C, R694H,
699 6 E699D, E699D,
695 6
702 7
5 7
701 7
680 8
677 8 M677T,
681 8 R681W,
696 9 R696H, R696C,
693 9 L693X,
684 9
4 9
3 9
700 9
6 9 G6R,
691 10
689 10
692 11
7 11
690 11
703 11
720 11
673 11
544 11 E544A, E544fsX,
683 11
403 12
704 12 A704T, A704V,
724 12 L724X,
678 12
676 12 Q676X, Q676fsX,
685 13 R685H, R685C, R685P,
705 13 W705fsX, W705X,
728 13
674 13 H674fsX, H674Y,
481 13
682 13 E682X,
706 13 S706C, S706F,
540 13 D540fsX,
716 13 V716G,
402 13 H402R,
764 14
727 14
541 14 R541H, R541C,
476 14 V476I,
679 14 R679Q, R679W,
719 14
8 14
767 14 D767X,
765 14
766 14
721 14 P721L,
687 15
543 15 S543fsX,
675 15
545 15
717 15 L717P,
688 15
482 15 V482A,