KCNH2 Variant L769P Detail

We estimate the penetrance of LQTS for KCNH2 L769P is 63%. We are unaware of any observations of this variant in individuals. L769P is not present in gnomAD. L769P 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 L769P around 63% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.809 1.0 -3 0.981 63
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.

L769P has 73 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
769 0
770 4
768 5
822 5 V822L, V822M, V822L,
723 6 C723G, C723X, C723R,
767 7 D767X,
771 7 H771R, H771fsX,
780 7
763 8
823 8 R823T, R823Q, R823fsX, R823W,
824 8
761 8
821 9 D821E, D821E,
830 9
787 9
805 9 F805S, F805C,
766 9
722 9
721 9 P721L,
764 9
832 9
778 10 A778T,
828 10
724 10 L724X,
820 10 G820R, G820R,
774 10 D774Y, D774X,
789 10
776 11 L776P, L776I,
762 11
772 11
788 11 E788D, E788K, E788D,
765 11
790 11
777 12
752 12 R752P, R752W, R752Q,
782 12 I782N, I782fsX,
806 12 G806R, G806R,
818 12 S818W, S818A, S818L,
700 12
825 12
779 12
696 12 R696H, R696C,
799 12 L799sp,
831 12
726 12
862 13 L862P,
786 13
829 13 D829E, D829E, D829A,
725 13 Q725R, Q725fsX,
760 13
775 13
826 13 T826A, T826I,
759 13 K759N, K759N,
773 13
833 13
781 13
727 13
834 13 H834R,
749 14
797 14 A797T,
819 14 N819K, N819K,
720 14
860 14
785 14 G785fsX, G785D, G785S,
804 14
827 14
800 14
803 14 D803X, D803Y,
748 15
703 15
783 15 S783P,
807 15 E807X,
699 15 E699D, E699D,