KCNH2 Variant G766A Detail

We estimate the penetrance of LQTS for KCNH2 G766A is 45%. We are unaware of any observations of this variant in individuals. G766A is not present in gnomAD. G766A 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G766A around 45% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.836 0.997 0 0.975 54
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 6 4 -
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.

G766A has 63 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
766 0
767 3 D767X,
765 4
824 5
764 6
823 6 R823W, R823Q, R823fsX, R823T,
768 6
7 7
10 7
825 7
763 8
696 8 R696C, R696H,
8 9
9 9 A9T, A9V,
826 9 T826A, T826I,
699 9 E699D, E699D,
769 9
822 9 V822L, V822L, V822M,
828 10
827 10
788 10 E788K, E788D, E788D,
787 10
11 10 Q11H, Q11L, Q11H,
12 11 N12D,
700 11
13 11 T13N,
723 11 C723X, C723R, C723G,
6 11 G6R,
695 11
786 11
724 11 L724X,
821 11 D821E, D821E,
481 12
703 12
790 12
770 12
771 12 H771fsX, H771R,
692 12
762 12
693 13 L693X,
789 13
721 13 P721L,
697 13 L697X,
727 13
785 13 G785S, G785D, G785fsX,
482 13 V482A,
761 13
830 13
480 13 E480V,
5 14
793 14 D793N,
16 14 D16A,
829 14 D829E, D829A, D829E,
698 14 E698K, E698X,
479 14
795 14 V795I,
799 15 L799sp,
15 15 L15V,
797 15 A797T,
820 15 G820R, G820R,
704 15 A704V, A704T,
798 15 I798fsX,
14 15