KCNH2 Variant L776R Detail

We estimate the penetrance of LQTS for KCNH2 L776R is 46%. We are unaware of any observations of this variant in individuals. L776R is not present in gnomAD. L776R 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L776R around 46% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.719 0.999 -2 0.953 50
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 6 4 -
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.

L776R has 58 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
776 0 L776I, L776P,
777 5
816 5 G816V,
775 5
778 5 A778T,
807 6 E807X,
806 6 G806R, G806R,
818 6 S818W, S818A, S818L,
774 7 D774X, D774Y,
862 7 L862P,
815 7
817 8
835 8 R835Q, R835W, R835fsX,
770 8
779 8
773 8
780 8
805 9 F805C, F805S,
834 10 H834R,
820 10 G820R, G820R,
808 10
861 10 N861I, N861H,
772 10
809 10
819 10 N819K, N819K,
812 10 Y812S,
771 10 H771fsX, H771R,
833 11
769 11
863 11 R863X, R863P,
844 11 M844V,
832 11
822 11 V822L, V822L, V822M,
749 12
821 12 D821E, D821E,
860 12
814 12
836 12
845 12
722 12
858 12 I858T, I858V,
813 12
804 13
838 13 L838R,
723 13 C723X, C723R, C723G,
789 13
781 14
811 14
837 14 D837N, D837G, D837Y,
753 14 A753S,
768 14
752 14 R752Q, R752P, R752W,
750 14 C750X,
839 14
859 14 T859R, T859M,
810 14
841 15 V841L, V841L,
747 15