KCNH2 Variant A726P Detail

We estimate the penetrance of LQTS for KCNH2 A726P is 16%. We are unaware of any observations of this variant in individuals. A726P is not present in gnomAD. A726P 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 A726P around 16% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.834 0.978 -1 0.888 18
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.

A726P 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
726 0
752 4 R752P, R752W, R752Q,
727 5
729 5
725 5 Q725R, Q725fsX,
728 5
756 6 M756V,
730 6
724 6 L724X,
723 6 C723G, C723X, C723R,
755 6
722 7
753 8 A753S,
721 8 P721L,
751 9 L751V,
717 9 L717P,
732 9
749 9
731 10 H731R,
733 10
754 10
720 10
771 10 H771R, H771fsX,
693 10 L693X,
768 10
696 11 R696H, R696C,
748 11
757 11
758 11
750 11 C750X,
774 12 D774Y, D774X,
697 12 L697X,
737 12 L737P,
770 12
769 12
719 13
734 13 R734H, R734C,
689 13
718 13
716 13 V716G,
687 13
767 13 D767X,
714 13
759 13 K759N, K759N,
683 13
772 13
692 13
700 13
690 14
747 14
775 14
773 14
841 14 V841L, V841L,
736 14
760 14
821 15 D821E, D821E,
738 15 Q738X,
713 15 M713V,
743 15
735 15 S735L,