KCNH2 Variant E788A Detail

We estimate the penetrance of LQTS for KCNH2 E788A is 62%. We are unaware of any observations of this variant in individuals. E788A is not present in gnomAD. E788A 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 E788A around 62% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.661 0.997 -1 0.952 68
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.

E788A has 72 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
788 0 E788D, E788K, E788D,
797 5 A797T,
787 5
798 5 I798fsX,
789 5
825 6
795 6 V795I,
790 6
824 6
823 7 R823Q, R823fsX, R823W, R823T,
786 7
12 7 N12D,
799 7 L799sp,
822 7 V822L, V822M, V822L,
796 8 V796L, V796Del, V796L,
15 8 L15V,
42 8 I42N,
13 9 T13N,
800 10
16 10 D16A,
10 10
794 10 V794D, V794I,
826 10 T826A, T826I,
821 10 D821E, D821E,
766 10
11 10 Q11L, Q11H, Q11H,
43 10 Y43C, Y43D,
785 10 G785D, G785fsX, G785S,
14 10
828 11
860 11
31 11 I31S,
820 11 G820R, G820R,
765 11
793 11 D793N,
767 11 D767X,
768 11
769 11
805 11 F805S, F805C,
19 12 I19F,
33 12 N33T,
791 12 R791W, R791Q,
782 12 I782fsX, I782N,
803 12 D803Y, D803X,
763 12
770 12
124 12 M124R, M124T,
792 12
60 12 M60T,
32 13 A32T,
859 13 T859M, T859R,
41 13 V41A,
9 13 A9T, A9V,
764 13
17 13
18 13 I18M,
44 13 C44X, C44F, C44W,
40 13
819 14 N819K, N819K,
801 14 K801T,
56 14 R56Q,
771 14 H771R, H771fsX,
830 14
61 14 Q61R,
123 14
780 14
862 14 L862P,
827 14
804 15
36 15 V36X,
829 15 D829A, D829E, D829E,
806 15 G806R, G806R,