KCNH2 Variant H731P Detail

We estimate the penetrance of LQTS for KCNH2 H731P is 71%. We are unaware of any observations of this variant in individuals. H731P is not present in gnomAD. H731P 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 H731P around 71% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.793 0.999 -2 0.93 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 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.

H731P has 52 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
731 0 H731R,
732 4
734 5 R734C, R734H,
730 6
728 6
689 6
690 7
733 7
687 7
729 7
727 7
693 8 L693X,
688 8
735 9 S735L,
726 10
738 10 Q738X,
692 10
684 10
683 10
737 10 L737P,
755 11
686 11
736 11
694 11 R694C, R694H,
691 11
724 12 L724X,
697 12 L697X,
752 12 R752Q, R752P, R752W,
760 12
725 12 Q725fsX, Q725R,
696 12 R696C, R696H,
831 12
751 13 L751V,
717 13 L717P,
758 13
756 13 M756V,
739 13 H739fsX,
713 13 M713V,
783 14 S783P,
720 14
695 14
829 14 D829E, D829A, D829E,
784 14 R784W, R784G, R784Q,
754 14
685 14 R685H, R685C, R685P,
680 14
723 14 C723X, C723R, C723G,
716 14 V716G,
759 14 K759N, K759N,
748 15
707 15
753 15 A753S,