KCNH2 Variant F781C Detail

We estimate the penetrance of LQTS for KCNH2 F781C is 54%. We are unaware of any observations of this variant in individuals. F781C is not present in gnomAD. F781C 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F781C around 54% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.715 1.0 -3 0.942 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 5 5 -
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.

F781C has 73 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
781 0
804 5
831 5
782 6 I782N, I782fsX,
779 6
736 6
780 6
805 7 F805C, F805S,
803 7 D803Y, D803X,
830 8
833 8
758 8
832 8
783 8 S783P,
802 8
740 8 C740W, C740G,
735 9 S735L,
743 9
733 10
858 10 I858V, I858T,
778 10 A778T,
856 10
806 10 G806R, G806R,
737 10 L737P,
742 10
859 10 T859R, T859M,
761 10
759 11 K759N, K759N,
800 11
760 11
799 11 L799sp,
829 11 D829E, D829E, D829A,
754 11
852 11
801 11 K801T,
838 11 L838R,
741 12 K741R,
787 12
739 12 H739fsX,
857 12 E857X,
755 12
834 12 H834R,
828 12
784 13 R784G, R784Q, R784W,
785 13 G785fsX, G785S, G785D,
853 13 W853X,
860 13
769 13
808 13
807 13 E807X,
738 13 Q738X,
757 13
732 13
855 13 S855R, S855R, S855R,
777 13
56 13 R56Q,
762 14
776 14 L776I, L776P,
734 14 R734H, R734C,
837 14 D837N, D837Y, D837G,
809 14
751 14 L751V,
763 14
744 14 R744X, R744Q, R744fsX, R744P, R744G,
835 14 R835Q, R835fsX, R835W,
822 14 V822M, V822L, V822L,
862 14 L862P,
786 14
729 14
861 14 N861H, N861I,
730 15
770 15
753 15 A753S,