KCNH2 Variant C566Y Detail

We estimate the penetrance of LQTS for KCNH2 C566Y is 51%. We are unaware of any observations of this variant in individuals. C566Y is not present in gnomAD. C566Y 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 C566Y around 51% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-10.726 0.989 -3 0.971 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 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.

C566Y has 62 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
566 0 C566G, C566S, C566R, C566F, C566S,
565 4
567 5 I567M, I567T,
562 6 H562Q, H562Q, H562R, H562P,
426 6 P426H,
430 6
564 6 L564L,
569 7 Y569H, Y569C, Y569X,
431 7 F431L, F431L, F431L,
563 7 W563X, W563C, W563G, W563C,
611 7 Y611D,
570 7
614 8 A614T, A614V,
427 8 Y427C, Y427H, Y427S,
561 8 A561V, A561P, A561T,
568 8 W568C, W568C,
429 8 A429P, A429V,
615 9 L615V, L615F,
618 9 T618S, T618S,
423 10
428 10 S428fsX, S428X, S428L,
571 10 I571V, I571L,
425 10
610 10
559 10 L559F, L559H,
560 11 I560fsX, I560M,
422 11 A422T,
640 11 F640L, F640V, F640L, F640L, F640Del,
612 11 V612L, V612A, V612L,
573 11
613 11 T613A, T613L, T613K, T613M,
572 11 G572S, G572R, G572C, G572D,
617 11 F617V, F617L, F617L, F617L,
424 11
432 11
558 12 A558V, A558P, A558E,
607 12
585 12 W585C, W585C,
574 12 M574V, M574L, M574L,
526 12
619 12
609 13 D609N, D609G,
529 13
644 13 V644F, V644I,
523 13
586 13 L586M,
608 14
421 14 T421M, T421fsX,
637 14 E637G, E637X, E637K,
616 14 Y616S,
622 14 L622F,
522 14 G522E,
643 14
525 14 K525N, K525N,
621 14 S621N, S621R, S621R, S621R,
557 15
641 15 S641F, S641P,
636 15
606 15 S606P, S606F, S606Del,
420 15 Y420C,
642 15 I642Del, I642V,
620 15 S620I, S620G,