KCNH2 Variant Y569H

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y569H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

41%

90% CI: 18.5% – 65.2%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y569H 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 10%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-4.734 0.975 2 0.962 88

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
10862094 2000 1 0 1
29622001 2018 1 0 1
Literature, cohort, and gnomAD – 1 0 1 –
Variant features alone – 10 7 3 –

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 Y569H.
Neighbour residue Distance (Å) Observed variants
569 0 Y569H, Y569C, Y569X,
570 5
573 5
431 5 F431L, F431L, F431L,
610 6
572 6 G572S, G572R, G572C, G572D,
430 6
566 7 C566S, C566R, C566G, C566S, C566F,
568 7 W568C, W568C,
571 7 I571L, I571V,
565 7
586 8 L586M,
585 8 W585C, W585C,
614 8 A614T, A614V,
567 8 I567T, I567M,
611 9 Y611D,
607 9
574 9 M574L, M574V, M574L,
613 10 T613A, T613L, T613K, T613M,
427 10 Y427H, Y427S, Y427C,
429 10 A429P, A429V,
432 10
609 10 D609N, D609G,
605 11 P605L,
612 11 V612L, V612L, V612A,
426 11 P426H,
576 11
606 11 S606Del, S606P, S606F,
564 11 L564L,
615 11 L615V, L615F,
575 11 E575K,
589 11 L589P,
562 11 H562P, H562R, H562Q, H562Q,
637 12 E637K, E637G, E637X,
428 12 S428fsX, S428X, S428L,
617 12 F617L, F617V, F617L, F617L,
640 12 F640L, F640V, F640Del, F640L, F640L
584 12 G584S, G584R, G584C,
587 12
618 12 T618S, T618S,
608 13
604 13 G604S, G604C, G604D,
636 13
630 13 V630I, V630T, V630A,
561 13 A561T, A561P, A561V,
563 13 W563G, W563C, W563C, W563X,
597 14 Y597H, Y597C,
588 14 N588D, N588K, N588K,
616 14 Y616S,
634 14 T634P, T634A, T634S, T634S, T634I,
590 14 G590D, G590V,
425 14
603 14 G603D,
631 15 S631F,
632 15 P632A, P632S,
523 15
423 15