KCNH2 Variant L754V Detail

We estimate the penetrance of LQTS for KCNH2 L754V is 24%. We are unaware of any observations of this variant in individuals. L754V is not present in gnomAD. L754V has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L754V around 24% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.918 0.994 1 0.905 35
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 8 2 -
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.

L754V has 68 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
754 0
753 4 A753S,
755 5
751 6 L751V,
758 6
757 6
750 6 C750X,
841 6 V841L, V841L,
838 7 L838R,
756 7 M756V,
743 8
749 8
737 8 L737P,
752 9 R752Q, R752W, R752P,
833 9
733 9
842 9
837 9 D837G, D837N, D837Y,
845 9
729 9
848 9
730 9
726 10
736 10
852 10
747 10
746 10 A746S, A746X,
840 11 E840Q,
759 11 K759N, K759N,
839 11
781 11
742 11
844 11 M844V,
748 11
831 12
779 12
834 12 H834R,
832 12
745 12 G745X, G745A,
774 12 D774X, D774Y,
849 12
732 12
843 12
740 13 C740G, C740W,
775 13
725 13 Q725fsX, Q725R,
853 13 W853X,
773 13
735 13 S735L,
727 13
722 13
836 13
728 13
738 13 Q738X,
760 14
856 14
851 14
846 14 P846T, P846S,
778 14 A778T,
744 14 R744Q, R744X, R744P, R744G, R744fsX,
835 14 R835W, R835fsX, R835Q,
771 14 H771R, H771fsX,
731 14 H731R,
723 14 C723X, C723G, C723R,
734 14 R734C, R734H,
780 14
809 15
772 15