KCNH2 Variant F720I Detail

We estimate the penetrance of LQTS for KCNH2 F720I is 42%. We are unaware of any observations of this variant in individuals. F720I is not present in gnomAD. F720I 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 F720I around 42% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.771 0.947 0 0.902 51
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.

F720I has 61 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
720 0
719 4
721 5 P721L,
717 5 L717P,
724 6 L724X,
725 6 Q725R, Q725fsX,
700 6
716 6 V716G,
697 7 L697X,
718 8
701 8
728 8
715 9 A715A, A715T, A715sp, A715V,
723 9 C723G, C723X, C723R,
680 9
722 9
683 10
704 10 A704T, A704V,
726 10
696 10 R696H, R696C,
727 10
693 11 L693X,
676 11 Q676X, Q676fsX,
714 11
729 11
698 11 E698K, E698X,
699 11 E699D, E699D,
679 12 R679Q, R679W,
756 12 M756V,
713 12 M713V,
703 12
684 12
702 12
677 12 M677T,
767 12 D767X,
689 13
694 13 R694H, R694C,
764 13
768 13
761 13
687 13
705 14 W705fsX, W705X,
712 14 D712N,
708 14
752 14 R752P, R752W, R752Q,
732 14
769 14
763 14
695 14
762 14
731 14 H731R,
712 14 D712N,
710 14
730 14
681 14 R681W,
673 15
755 15
707 15
706 15 S706C, S706F,
711 15 I711V,
682 15 E682X,