KCNH2 Variant D727E Detail

We estimate the penetrance of LQTS for KCNH2 D727E is 21%. We are unaware of any observations of this variant in individuals. D727E is not present in gnomAD. D727E 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D727E around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.891 0.887 1 0.824 31
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 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.

D727E has 60 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
727 0
726 5
728 5
730 5
724 5 L724X,
693 6 L693X,
752 7 R752Q, R752P, R752W,
729 7
731 7 H731R,
696 7 R696C, R696H,
723 8 C723X, C723R, C723G,
725 8 Q725fsX, Q725R,
692 9
732 9
697 9 L697X,
690 9
755 10
689 10
768 10
721 10 P721L,
756 10 M756V,
720 10
733 10
751 11 L751V,
771 11 H771fsX, H771R,
722 11
717 11 L717P,
748 11
734 11 R734C, R734H,
753 12 A753S,
695 12
749 12
767 12 D767X,
687 12
694 12 R694C, R694H,
737 12 L737P,
683 12
691 12
700 12
684 13
754 13
769 13
766 13
699 13 E699D, E699D,
738 13 Q738X,
770 13
716 14 V716G,
719 14
698 14 E698K, E698X,
758 14
750 14 C750X,
774 14 D774X, D774Y,
823 14 R823W, R823Q, R823fsX, R823T,
688 14
735 14 S735L,
821 14 D821E, D821E,
772 15
680 15
736 15
757 15