KCNH2 Variant F656Y Detail

We estimate the penetrance of LQTS for KCNH2 F656Y is 34%. We are unaware of any observations of this variant in individuals. F656Y is not present in gnomAD. F656Y 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F656Y around 34% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.905 1.0 3 0.935 52
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 7 3 -
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.

F656Y 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
656 0 F656L, F656L, F656L,
655 4
652 5 Y652X,
659 5
657 6 G657V, G657S,
649 6
653 6
653 7
654 7
650 7 L650X,
660 7 S660L,
658 7
554 7
557 8
651 8 M651K,
553 8 L553V,
654 9
648 9 G648A,
623 10 T623I,
550 10
646 10
652 10 Y652X,
661 10 A661V,
648 10 G648A,
622 10 L622F,
662 10
556 10
650 11 L650X,
651 11 M651K,
663 11
649 11
660 11 S660L,
647 11
657 12 G657V, G657S,
555 12
558 12 A558V, A558P, A558E,
624 12 S624R, S624R, S624R, S624N,
560 12 I560fsX, I560M,
619 12
549 12 V549M,
645 12 M645I, M645L, M645I, M645L, M645I, M645V, M645R,
552 12 L552S,
655 13
656 13 F656L, F656L, F656L,
656 13 F656L, F656L, F656L,
647 13
652 13 Y652X,
664 13 Q664X,
624 13 S624R, S624R, S624R, S624N,
663 13
551 13 F551L, F551L, F551L,
657 14 G657V, G657S,
664 14 Q664X,
659 14
622 14 L622F,
561 14 A561V, A561P, A561T,
658 14
621 14 S621N, S621R, S621R, S621R,
644 14 V644F, V644I,
559 14 L559F, L559H,
623 15 T623I,
620 15 S620I, S620G,
625 15 V625E,
661 15 A661V,
547 15 A547T,
665 15 R665Q,