KCNH2 Variant W563C Detail

We estimate the penetrance of LQTS for KCNH2 W563C is 19%. This variant was found in a total of 5 carriers in 2 papers or gnomAD (version 4), 3 had LQTS. W563C is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 14%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. W563C 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 W563C around 19% (5/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-12.46 1.0 -3 0.919 70
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
Japan Cohort 2020 3 0 3
29766883 2016 2 2
LITERATURE, COHORT, AND GNOMAD: - 5 2 3 -
VARIANT FEATURES ALONE: - 10 8 2 -
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.

W563C has 59 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
563 0 W563C, W563X, W563C, W563G,
559 5 L559F, L559H,
562 5 H562P, H562R, H562Q, H562Q,
560 6 I560fsX, I560M,
422 6 A422T,
561 6 A561V, A561T, A561P,
564 6 L564L,
426 7 P426H,
566 7 C566S, C566G, C566R, C566F, C566S,
423 8
565 8
558 8 A558P, A558V, A558E,
567 8 I567M, I567T,
529 8
425 9
556 9
421 10 T421fsX, T421M,
532 10
618 11 T618S, T618S,
419 11
557 11
526 11
615 11 L615V, L615F,
555 11
424 11
427 11 Y427S, Y427H, Y427C,
430 11
611 12 Y611D,
429 12 A429V, A429P,
619 12
418 12
647 12
428 12 S428X, S428fsX, S428L,
614 12 A614V, A614T,
644 12 V644I, V644F,
640 13 F640V, F640Del, F640L, F640L, F640L,
622 13 L622F,
431 13 F431L, F431L, F431L,
530 13
651 13 M651K,
420 13 Y420C,
570 13
527 13
568 13 W568C, W568C,
528 13 R528P, R528X, R528W,
643 13
569 13 Y569C, Y569H, Y569X,
531 14 R531W, R531Del, R531Q,
533 14
648 14 G648A,
617 14 F617L, F617L, F617L, F617V,
552 14 L552S,
525 15 K525N, K525N,
554 15
571 15 I571L, I571V,
523 15
535 15 V535M,
553 15 L553V,
621 15 S621N, S621R, S621R, S621R,