KCNH2 Variant L779M Detail

We estimate the penetrance of LQTS for KCNH2 L779M is 36%. We are unaware of any observations of this variant in individuals. L779M is not present in gnomAD. L779M 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L779M around 36% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.862 0.987 2 0.797 51
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 7 3 -
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.

L779M has 71 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
779 0
778 5 A778T,
780 5
833 5
781 6
806 6 G806R, G806R,
805 6 F805C, F805S,
804 7
832 7
834 8 H834R,
777 8
838 8 L838R,
807 8 E807X,
776 8 L776I, L776P,
835 8 R835Q, R835fsX, R835W,
858 8 I858V, I858T,
809 9
808 9
758 9
831 10
856 10
853 10 W853X,
837 10 D837N, D837Y, D837G,
862 11 L862P,
782 11 I782N, I782fsX,
852 11
759 11 K759N, K759N,
830 11
859 11 T859R, T859M,
861 11 N861H, N861I,
839 11
803 11 D803Y, D803X,
754 12
736 12
836 12
757 12
860 12
743 12
770 12
761 12
816 12 G816V,
769 12
810 13
742 13
857 13 E857X,
775 13
842 13
740 13 C740W, C740G,
760 13
799 13 L799sp,
815 13
822 13 V822M, V822L, V822L,
841 13 V841L, V841L,
755 14
818 14 S818L, S818A, S818W,
733 14
802 14
812 14 Y812S,
783 14 S783P,
787 14
737 14 L737P,
855 14 S855R, S855R, S855R,
774 14 D774X, D774Y,
811 14
840 14 E840Q,
813 15
800 15
735 15 S735L,
789 15
820 15 G820R, G820R,
848 15