KCNH2 Variant F743L Detail

We estimate the penetrance of LQTS for KCNH2 F743L is 17%. We are unaware of any observations of this variant in individuals. F743L is not present in gnomAD. F743L 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F743L around 17% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.469 0.968 0 0.927 22
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 9 1 -
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.

F743L has 57 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
743 0
742 4
737 5 L737P,
740 6 C740G, C740W,
736 7
744 7 R744Q, R744X, R744P, R744G, R744fsX,
745 7 G745X, G745A,
852 7
751 7 L751V,
746 7 A746S, A746X,
754 8
741 8 K741R,
848 8
738 9 Q738X,
856 9
750 9 C750X,
855 9 S855R, S855R, S855R,
781 9
851 9
739 9 H739fsX,
735 10 S735L,
733 10
758 10
747 10
755 10
853 11 W853X,
753 11 A753S,
730 11
804 11
838 11 L838R,
749 11
849 12
842 12
748 12
802 12
831 12
841 12 V841L, V841L,
779 12
854 12
833 12
857 12 E857X,
845 12
734 13 R734C, R734H,
752 13 R752Q, R752W, R752P,
757 13
858 14 I858T, I858V,
803 14 D803Y, D803X,
729 14
782 14 I782fsX, I782N,
850 14 D850N,
783 14 S783P,
732 14
756 14 M756V,
847 15
726 15
780 15
832 15