KCNH2 Variant Y611D

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y611D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

32%

90% CI: 16.2% – 62.3%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y611D 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 4%. 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 (%)
-9.484 1.0 -3 0.969 83

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 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 Y611D.
Neighbour residue Distance (Å) Observed variants
611 0 Y611D,
612 5 V612L, V612L, V612A,
615 6 L615V, L615F,
614 6 A614T, A614V,
565 6
427 7 Y427H, Y427S, Y427C,
562 7 H562P, H562R, H562Q, H562Q,
609 7 D609N, D609G,
608 7
566 7 C566S, C566R, C566G, C566S, C566F,
431 7 F431L, F431L, F431L,
613 7 T613A, T613L, T613K, T613M,
610 7
607 8
569 9 Y569H, Y569C, Y569X,
561 9 A561T, A561P, A561V,
639 10 I639F, I639N,
635 10 N635I,
423 10
430 10
426 10 P426H,
638 10 K638E, K638D, K638Del, K638R,
618 10 T618S, T618S,
606 10 S606Del, S606P, S606F,
616 10 Y616S,
642 11 I642V, I642Del,
568 11 W568C, W568C,
564 11 L564L,
424 11
619 11
617 11 F617L, F617V, F617L, F617L,
558 11 A558P, A558E, A558V,
567 11 I567T, I567M,
428 11 S428fsX, S428X, S428L,
563 12 W563G, W563C, W563C, W563X,
559 12 L559F, L559H,
585 12 W585C, W585C,
570 12
429 12 A429P, A429V,
432 13
605 13 P605L,
586 13 L586M,
422 13 A422T,
425 13
589 13 L589P,
636 13
560 13 I560fsX, I560M,
641 14 S641P, S641F,
630 14 V630I, V630T, V630A,
573 14
634 14 T634P, T634A, T634S, T634S, T634I,
620 14 S620G, S620I,
572 14 G572S, G572R, G572C, G572D,
571 14 I571L, I571V,
645 15 M645L, M645V, M645L, M645R, M645I, M645I, M645I
643 15
632 15 P632A, P632S,
557 15