KCNH2 Variant K759N Detail

We estimate the penetrance of LQTS for KCNH2 K759N is 8%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. K759N is present in 1 alleles in gnomAD. K759N has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K759N around 8% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.172 0.37 0 0.772 6
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: - 1 1 0 -
VARIANT FEATURES ALONE: - 10 10 0 -
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.

K759N has 55 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
759 0 K759N, K759N,
832 5
760 5
758 5
833 6
761 7
831 7
834 8 H834R,
757 8
755 9
830 9
733 9
837 9 D837N, D837Y, D837G,
756 9 M756V,
714 10
729 10
780 10
732 10
778 10 A778T,
781 11
779 11
754 11
762 11
713 11 M713V,
777 12
838 12 L838R,
722 12
717 12 L717P,
736 12
721 12 P721L,
753 13 A753S,
829 13 D829E, D829E, D829A,
769 13
728 13
836 13
725 13 Q725fsX, Q725R,
726 13
763 13
782 14 I782N, I782fsX,
687 14
730 14
735 14 S735L,
835 14 R835Q, R835fsX, R835W,
783 14 S783P,
805 14 F805C, F805S,
719 14
707 14
737 14 L737P,
715 14 A715sp, A715A, A715T, A715V,
718 14
731 14 H731R,
841 15 V841L, V841L,
723 15 C723R, C723G, C723X,
712 15 D712N,
840 15 E840Q,