KCNH2 Variant H762R Detail

We estimate the penetrance of LQTS for KCNH2 H762R is 12%. We are unaware of any observations of this variant in individuals. H762R is not present in gnomAD. H762R 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H762R around 12% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.781 0.597 0 0.828 14
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 9 1 -
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.

H762R has 62 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
762 0
763 5
761 5
829 5 D829A, D829E, D829E,
707 6
830 6
760 7
828 7
764 7
703 7
827 8
704 8 A704T, A704V,
831 9
784 9 R784Q, R784G, R784W,
700 9
708 10
783 10 S783P,
767 10 D767X,
826 10 T826I, T826A,
765 10
686 10
706 11 S706F, S706C,
785 11 G785D, G785S, G785fsX,
759 11 K759N, K759N,
824 11
832 11
782 11 I782fsX, I782N,
769 11
687 12
721 12 P721L,
713 12 M713V,
732 12
787 12
766 12
780 12
786 13
479 13
733 13
699 13 E699D, E699D,
825 13
709 13
781 14
719 14
768 14
705 14 W705fsX, W705X,
735 14 S735L,
478 14 A478D,
723 14 C723X, C723R, C723G,
711 14 I711V,
701 14
758 14
720 14
702 14
801 14 K801T,
800 14
724 14 L724X,
710 15
688 15
714 15
822 15 V822M, V822L, V822L,
736 15
805 15 F805C, F805S,