KCNH2 Variant W563C

Summary of observed carriers, functional annotations, and structural context for KCNH2 W563C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

19%

90% CI: 16.9% – 56.2%

5/15 effective observations

Total carriers

5

3 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

W563C has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

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.

Variant features alone are equivalent to phenotyping 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-12.46 1.0 -3 0.919 70

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source 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 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that 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 15Å window.

Previously observed variants near W563C.
Neighbour residue Distance (Å) Observed variants
563 0 W563G, W563C, W563C, W563X,
559 5 L559F, L559H,
562 5 H562P, H562R, H562Q, H562Q,
560 6 I560fsX, I560M,
422 6 A422T,
561 6 A561T, A561P, A561V,
564 6 L564L,
426 7 P426H,
566 7 C566S, C566R, C566G, C566S, C566F,
423 8
565 8
558 8 A558P, A558E, A558V,
567 8 I567T, I567M,
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 Y427H, Y427S, Y427C,
430 11
611 12 Y611D,
429 12 A429P, A429V,
619 12
418 12
647 12
428 12 S428fsX, S428X, S428L,
614 12 A614T, A614V,
644 12 V644I, V644F,
640 13 F640L, F640V, F640Del, 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 R528W, R528X, R528P,
643 13
569 13 Y569H, Y569C, Y569X,
531 14 R531W, R531Del, R531Q,
533 14
648 14 G648A,
617 14 F617L, F617V, F617L, F617L,
552 14 L552S,
525 15 K525N, K525N,
554 15
571 15 I571L, I571V,
523 15
535 15 V535M,
553 15 L553V,
621 15 S621R, S621N, S621R, S621R,