KCNH2 Variant E722D Detail

We estimate the penetrance of LQTS for KCNH2 E722D is 16%. We are unaware of any observations of this variant in individuals. E722D is not present in gnomAD. E722D has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E722D around 16% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.712 0.614 2 0.718 26
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 9 1 -
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.

E722D has 54 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
722 0
723 5 C723G, C723X, C723R,
721 5 P721L,
725 5 Q725R, Q725fsX,
756 7 M756V,
726 7
724 8 L724X,
752 9 R752P, R752W, R752Q,
769 9
720 9
753 10 A753S,
770 10
717 10 L717P,
777 10
719 10
771 11 H771R, H771fsX,
768 11
718 11
832 11
774 11 D774Y, D774X,
729 11
727 11
775 11
755 11
728 11
834 11 H834R,
778 11 A778T,
761 11
757 12
749 12
776 12 L776P, L776I,
759 12 K759N, K759N,
700 12
780 12
767 13 D767X,
754 13
730 13
833 14
696 14 R696H, R696C,
716 14 V716G,
822 14 V822L, V822M, V822L,
714 14
751 14 L751V,
773 14
763 14
750 14 C750X,
772 14
760 14
697 14 L697X,
715 14 A715A, A715T, A715sp, A715V,
841 14 V841L, V841L,
830 15
821 15 D821E, D821E,
748 15