KCNH2 Variant F758L Detail

We estimate the penetrance of LQTS for KCNH2 F758L is 22%. We are unaware of any observations of this variant in individuals. F758L is not present in gnomAD. F758L 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 F758L around 22% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.836 0.55 0 0.832 30
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.

F758L has 66 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
758 0
755 5
833 5
759 5 K759N, K759N,
754 6
757 6
733 6
831 6
832 7
781 8
756 8 M756V,
729 8
760 8
736 8
753 9 A753S,
837 9 D837G, D837N, D837Y,
838 9 L838R,
834 9 H834R,
779 9
737 9 L737P,
732 9
780 10
743 10
751 10 L751V,
730 10
761 10
830 10
778 11 A778T,
735 11 S735L,
841 11 V841L, V841L,
726 11
750 12 C750X,
752 12 R752Q, R752W, R752P,
728 12
782 12 I782fsX, I782N,
740 13 C740G, C740W,
731 13 H731R,
783 13 S783P,
804 13
734 13 R734C, R734H,
852 13
725 13 Q725fsX, Q725R,
777 13
840 13 E840Q,
836 13
839 13
842 13
742 13
714 13
835 13 R835W, R835fsX, R835Q,
805 13 F805S, F805C,
749 13
829 14 D829A, D829E, D829E,
738 14 Q738X,
717 14 L717P,
762 14
727 14
848 14
687 15
856 15
713 15 M713V,
802 15
845 15
739 15 H739fsX,
853 15 W853X,
806 15 G806R, G806R,