KCNH2 Variant F557I Detail

We estimate the penetrance of LQTS for KCNH2 F557I is 58%. We are unaware of any observations of this variant in individuals. F557I is not present in gnomAD. F557I 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F557I around 58% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.751 0.997 0 0.912 66
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 5 5 -
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.

F557I has 65 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
557 0
558 5 A558V, A558P, A558E,
560 6 I560M, I560fsX,
554 6
556 6
619 7
561 7 A561P, A561T, A561V,
622 7 L622F,
651 7 M651K,
646 7
655 7
555 7
656 8 F656L, F656L, F656L,
559 8 L559F, L559H,
553 8 L553V,
649 8
652 8 Y652X,
623 8 T623I,
648 9 G648A,
618 9 T618S, T618S,
645 10 M645I, M645I, M645L, M645L, M645R, M645I, M645V,
650 10 L650X,
562 10 H562R, H562Q, H562Q, H562P,
564 11 L564L,
642 11 I642Del, I642V,
552 11 L552S,
615 11 L615F, L615V,
647 11
563 11 W563C, W563G, W563X, W563C,
654 11
659 11
648 11 G648A,
653 11
621 11 S621R, S621N, S621R, S621R,
550 11
620 11 S620I, S620G,
551 11 F551L, F551L, F551L,
647 12
644 12 V644I, V644F,
650 12 L650X,
649 12
643 12
624 12 S624R, S624R, S624R, S624N,
658 12
657 13 G657S, G657V,
565 13
653 13
644 13 V644I, V644F,
617 14 F617V, F617L, F617L, F617L,
419 14
423 14
422 14 A422T,
625 14 V625E,
549 14 V549M,
641 14 S641F, S641P,
616 14 Y616S,
660 14 S660L,
614 14 A614T, A614V,
651 14 M651K,
645 15 M645I, M645I, M645L, M645L, M645R, M645I, M645V,
566 15 C566F, C566R, C566G, C566S, C566S,
624 15 S624R, S624R, S624R, S624N,
652 15 Y652X,
611 15 Y611D,
646 15