KCNH2 Variant C566S

Summary of observed carriers, functional annotations, and structural context for KCNH2 C566S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

27%

3/16 effective observations

Total carriers

6

1 LQT2 · 5 unaffected

Functional studies

0

Publications with functional data

C566S 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 0%. 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 (%)
-9.751 0.999 -1 0.92 52

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
France Cohort 2020 6 5 1
Literature, cohort, and gnomAD – 6 5 1 –
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 C566S.
Neighbour residue Distance (Å) Observed variants
566 0 C566S, C566R, C566G, C566S, C566F,
565 4
567 5 I567T, I567M,
562 6 H562P, H562R, H562Q, H562Q,
426 6 P426H,
430 6
564 6 L564L,
569 7 Y569H, Y569C, Y569X,
431 7 F431L, F431L, F431L,
563 7 W563G, W563C, W563C, W563X,
611 7 Y611D,
570 7
614 8 A614T, A614V,
427 8 Y427H, Y427S, Y427C,
561 8 A561T, A561P, A561V,
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 I571L, I571V,
425 10
610 10
559 10 L559F, L559H,
560 11 I560fsX, I560M,
422 11 A422T,
640 11 F640L, F640V, F640Del, F640L, F640L,
612 11 V612L, V612L, V612A,
573 11
613 11 T613A, T613L, T613K, T613M,
572 11 G572S, G572R, G572C, G572D,
617 11 F617L, F617V, F617L, F617L,
424 11
432 11
558 12 A558P, A558E, A558V,
607 12
585 12 W585C, W585C,
574 12 M574L, M574V, M574L,
526 12
619 12
609 13 D609N, D609G,
529 13
644 13 V644I, V644F
523 13
586 13 L586M,
608 14
421 14 T421fsX, T421M,
637 14 E637K, E637G, E637X,
616 14 Y616S,
622 14 L622F,
522 14 G522E,
643 14
525 14 K525N, K525N,
621 14 S621R, S621N, S621R, S621R,
557 15
641 15 S641P, S641F,
636 15
606 15 S606Del, S606P, S606F,
420 15 Y420C,
642 15 I642V, I642Del,
620 15 S620G, S620I,