KCNH2 Variant H771P Detail

We estimate the penetrance of LQTS for KCNH2 H771P is 69%. We are unaware of any observations of this variant in individuals. H771P is not present in gnomAD. H771P 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 H771P around 69% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.727 0.999 -3 0.919 69
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.

H771P has 60 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
771 0 H771fsX, H771R,
770 4
772 5
821 5 D821E, D821E,
774 6 D774X, D774Y,
768 6
752 7 R752Q, R752P, R752W,
820 7 G820R, G820R,
822 7 V822M, V822L, V822L,
749 7
773 7
748 7
769 7
723 7 C723R, C723G, C723X,
818 8 S818L, S818A, S818W,
823 9 R823Q, R823T, R823W, R823fsX,
790 10
726 10
747 10
775 10
819 10 N819K, N819K,
776 10 L776I, L776P,
722 11
727 11
767 11 D767X,
750 11 C750X,
751 11 L751V,
789 11
724 11 L724X,
753 11 A753S,
817 12
862 12 L862P,
792 12
791 12 R791Q, R791W,
766 12
730 12
721 13 P721L,
824 13
777 13
780 13
696 13 R696C, R696H,
778 13 A778T,
805 13 F805C, F805S,
793 13 D793N,
725 13 Q725fsX, Q725R,
845 13
756 13 M756V,
816 13 G816V,
806 14 G806R, G806R,
746 14 A746S, A746X,
788 14 E788D, E788K, E788D,
787 14
755 14
754 14
763 14
729 14
794 14 V794I, V794D,
728 15
860 15
863 15 R863P, R863X,