KCNH2 Variant I782F Detail

We estimate the penetrance of LQTS for KCNH2 I782F is 67%. We are unaware of any observations of this variant in individuals. I782F is not present in gnomAD. I782F 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 I782F around 67% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.603 0.996 0 0.932 75
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.

I782F has 69 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
782 0 I782fsX, I782N,
783 5 S783P,
803 5 D803Y, D803X,
800 5
830 6
781 6
802 6
801 7 K801T,
799 7 L799sp,
785 7 G785D, G785fsX, G785S,
804 7
831 7
787 7
805 7 F805S, F805C,
829 7 D829A, D829E, D829E,
828 8
780 8
784 8 R784G, R784W, R784Q,
786 8
736 9
735 9 S735L,
859 10 T859M, T859R,
761 10
763 10
779 11
740 11 C740G, C740W,
832 11
762 11
56 11 R56Q,
798 11 I798fsX,
824 11
826 11 T826A, T826I,
760 12
858 12 I858T, I858V,
769 12
822 12 V822L, V822M, V822L,
806 12 G806R, G806R,
739 12 H739fsX,
788 12 E788D, E788K, E788D,
733 12
860 12
825 12
758 12
797 12 A797T,
789 12
833 13
778 13 A778T,
43 13 Y43C, Y43D,
737 13 L737P,
759 14 K759N, K759N,
764 14
44 14 C44X, C44F, C44W,
857 14 E857X,
856 14
827 14
743 14
741 14 K741R,
46 14 D46E, D46Y, D46E,
770 14
734 14 R734C, R734H,
16 14 D16A,
767 14 D767X,
742 14
732 15
60 15 M60T,
738 15 Q738X,
57 15 A57P,
765 15
823 15 R823Q, R823fsX, R823W, R823T,