KCNH2 Variant F617I Detail

We estimate the penetrance of LQTS for KCNH2 F617I is 72%. We are unaware of any observations of this variant in individuals. F617I is not present in gnomAD. F617I 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F617I around 72% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.691 0.997 0 0.943 80
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 3 7 -
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.

F617I has 84 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
617 0 F617V, F617L, F617L, F617L,
618 4 T618S, T618S,
620 5 S620I, S620G,
614 6 A614T, A614V,
621 6 S621N, S621R, S621R, S621R,
630 6 V630I, V630T, V630A,
568 6 W568C, W568C,
616 6 Y616S,
613 7 T613A, T613L, T613K, T613M,
615 7 L615V, L615F,
631 7 S631F,
565 8
641 8 S641F, S641P,
619 8
640 8 F640L, F640V, F640L, F640L, F640Del,
627 8 F627X, F627L, F627fsX, F627L, F627L,
632 8 P632S, P632A,
626 8 G626A, G626S, G626V,
585 8 W585C, W585C,
644 8 V644F, V644I,
564 8 L564L,
622 9 L622F,
627 9 F627X, F627L, F627fsX, F627L, F627L,
628 9 G628V, G628R, G628A, G628D, G628Del, G628S,
561 9 A561V, A561P, A561T,
637 9 E637G, E637X, E637K,
629 9 N629K, N629S, N629K, N629I, N629D, N629T,
625 10 V625E,
612 10 V612L, V612A, V612L,
623 10 T623I,
645 10 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
638 10 K638Del, K638E, K638D, K638R,
625 10 V625E,
642 11 I642Del, I642V,
645 11 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
567 11 I567M, I567T,
624 11 S624R, S624R, S624R, S624N,
611 11 Y611D,
626 11 G626A, G626S, G626V,
566 11 C566G, C566S, C566R, C566F, C566S,
641 11 S641F, S641P,
571 11 I571V, I571L,
638 12 K638Del, K638E, K638D, K638R,
632 12 P632S, P632A,
629 12 N629K, N629S, N629K, N629I, N629D, N629T,
616 12 Y616S,
569 12 Y569H, Y569C, Y569X,
643 12
642 12 I642Del, I642V,
633 12 N633D, N633I, N633S,
589 12 L589P,
586 12 L586M,
562 12 H562Q, H562Q, H562R, H562P,
628 12 G628V, G628R, G628A, G628D, G628Del, G628S,
588 13 N588K, N588K, N588D,
648 13 G648A,
610 13
560 13 I560fsX, I560M,
609 13 D609N, D609G,
636 13
620 13 S620I, S620G,
570 13
584 13 G584C, G584S, G584R,
572 13 G572S, G572R, G572C, G572D,
626 13 G626A, G626S, G626V,
634 13 T634S, T634I, T634S, T634P, T634A,
639 13 I639F, I639N,
631 13 S631F,
647 13
633 13 N633D, N633I, N633S,
558 14 A558V, A558P, A558E,
557 14
639 14 I639F, I639N,
592 14 Q592X,
621 14 S621N, S621R, S621R, S621R,
623 14 T623I,
624 14 S624R, S624R, S624R, S624N,
624 14 S624R, S624R, S624R, S624N,
563 14 W563X, W563C, W563G, W563C,
635 14 N635I,
628 15 G628V, G628R, G628A, G628D, G628Del, G628S,
646 15
646 15
644 15 V644F, V644I,