KCNH2 Variant Y780D Detail

We estimate the penetrance of LQTS for KCNH2 Y780D is 59%. We are unaware of any observations of this variant in individuals. Y780D is not present in gnomAD. Y780D 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y780D around 59% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.26 0.996 -3 0.975 60
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 5 5 -
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.

Y780D has 76 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
780 0
805 4 F805S, F805C,
779 5
778 5 A778T,
832 5
781 6
833 7
830 7
806 7 G806R, G806R,
769 7
831 8
804 8
782 8 I782N, I782fsX,
761 8
776 8 L776P, L776I,
770 9
777 9
834 9 H834R,
822 9 V822L, V822M, V822L,
759 10 K759N, K759N,
787 10
758 10
803 10 D803X, D803Y,
807 10 E807X,
862 11 L862P,
858 11 I858V, I858T,
760 11
799 11 L799sp,
859 11 T859M, T859R,
763 11
860 11
835 11 R835Q, R835W, R835fsX,
783 12 S783P,
828 12
789 12
829 12 D829E, D829E, D829A,
768 12
838 12 L838R,
736 12
800 12
722 12
808 12
762 12
774 13 D774Y, D774X,
820 13 G820R, G820R,
861 13 N861I, N861H,
818 13 S818W, S818A, S818L,
723 13 C723G, C723X, C723R,
824 13
775 13
771 13 H771R, H771fsX,
837 13 D837N, D837G, D837Y,
809 13
802 13
821 13 D821E, D821E,
767 13 D767X,
816 13 G816V,
856 14
733 14
785 14 G785fsX, G785D, G785S,
786 14
823 14 R823T, R823Q, R823fsX, R823W,
721 14 P721L,
757 14
788 14 E788D, E788K, E788D,
797 14 A797T,
819 14 N819K, N819K,
836 14
764 14
735 14 S735L,
754 14
801 15 K801T,
740 15 C740G, C740W,
772 15
743 15
755 15