KCNH2 Variant A763G Detail

We estimate the penetrance of LQTS for KCNH2 A763G is 27%. We are unaware of any observations of this variant in individuals. A763G is not present in gnomAD. A763G 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 A763G around 27% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.757 0.973 0 0.783 35
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.

A763G has 68 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
763 0
764 3
828 5
762 5
767 6 D767X,
824 6
765 7
761 7
830 7
827 7
829 7 D829E, D829A, D829E,
826 7 T826A, T826I,
766 8
769 8
703 8
787 9
700 9
825 9
768 9
785 9 G785S, G785D, G785fsX,
786 10
760 10
822 10 V822L, V822L, V822M,
707 10
782 10 I782fsX, I782N,
704 11 A704V, A704T,
823 11 R823W, R823Q, R823fsX, R823T,
784 11 R784W, R784G, R784Q,
831 11
783 11 S783P,
721 11 P721L,
699 11 E699D, E699D,
723 11 C723X, C723R, C723G,
780 11
832 12
770 12
788 12 E788K, E788D, E788D,
696 12 R696C, R696H,
7 12
724 12 L724X,
800 13
479 13
805 13 F805C, F805S,
799 13 L799sp,
10 13
706 13 S706F, S706C,
759 13 K759N, K759N,
481 14
720 14
801 14 K801T,
781 14
478 14 A478D,
708 14
722 14
9 14 A9T, A9V,
6 14 G6R,
789 14
480 14 E480V,
771 14 H771fsX, H771R,
702 14
803 14 D803X, D803Y,
16 14 D16A,
821 15 D821E, D821E,
13 15 T13N,
719 15
8 15
701 15
697 15 L697X,