KCNH2 Variant G806R Detail

We estimate the penetrance of LQTS for KCNH2 G806R is 84%. This variant was found in a total of 3 carriers in 2 papers or gnomAD, 3 had LQTS. G806R is not present in gnomAD. G806R 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G806R around 84% (10/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.434 1.0 -3 0.451 80
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
Italy Cohort 2020 2 0 2
France Cohort 2020 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 3 0 3 -
VARIANT FEATURES ALONE: - 10 3 7 -
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.

G806R has 65 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
806 0 G806R, G806R,
807 4 E807X,
862 5 L862P,
805 5 F805S, F805C,
861 6 N861I, N861H,
779 6
858 6 I858T, I858V,
776 6 L776I, L776P,
808 7
860 7
778 7 A778T,
780 7
804 7
859 8 T859M, T859R,
818 9 S818A, S818L, S818W,
816 9 G816V,
809 9
777 10
819 10 N819K, N819K,
781 10
770 10
820 10 G820R, G820R,
835 10 R835W, R835fsX, R835Q,
789 11
822 11 V822L, V822M, V822L,
833 11
812 11 Y812S,
863 11 R863X, R863P,
856 11
803 11 D803Y, D803X,
799 11 L799sp,
775 11
774 12 D774X, D774Y,
832 12
817 12
857 12 E857X,
769 12
853 12 W853X,
815 12
57 12 A57P,
782 12 I782fsX, I782N,
811 12
834 12 H834R,
810 13
787 13
773 13
797 13 A797T,
821 13 D821E, D821E,
61 13 Q61R,
838 13 L838R,
772 13
60 13 M60T,
830 13
771 14 H771R, H771fsX,
852 14
831 14
796 14 V796L, V796Del, V796L,
56 14 R56Q,
813 14
791 14 R791W, R791Q,
800 14
790 14
839 15
758 15
788 15 E788D, E788K, E788D,