KCNH2 Variant F686L Detail

We estimate the penetrance of LQTS for KCNH2 F686L is 19%. We are unaware of any observations of this variant in individuals. F686L is not present in gnomAD. F686L 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 F686L around 19% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.833 0.866 0 0.846 25
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.

F686L has 45 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
686 0
687 4
707 6
708 6
683 6
709 7
688 7
713 7 M713V,
684 8
711 8 I711V,
682 8 E682X,
685 8 R685H, R685C, R685P,
689 10
706 10 S706F, S706C,
732 10
710 10
762 10
704 11 A704V, A704T,
760 11
680 11
731 11 H731R,
712 11 D712N,
705 11 W705fsX, W705X,
716 12 V716G,
728 12
679 12 R679W, R679Q,
703 12
714 12
681 12 R681W,
829 13 D829E, D829A, D829E,
717 13 L717P,
678 13
690 13
729 13
694 13 R694C, R694H,
734 13 R734C, R734H,
715 13 A715sp, A715T, A715A, A715V,
761 13
733 14
784 14 R784W, R784G, R784Q,
697 14 L697X,
669 14 G669C, G669X, G669R,
693 14 L693X,
831 15
827 15