KCNH2 Variant A561T

Summary of observed carriers, functional annotations, and structural context for KCNH2 A561T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

67%

90% CI: 62.3% – 85.2%

28/38 effective observations

Total carriers

28

25 LQT2 · 3 unaffected

Functional studies

2

Publications with functional data

A561T has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 49% of WT with a standard error of 39%. 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 (%)
-3.834 1.0 0 0.959 77

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
28438721 2017 1 0 1
Japan Cohort 2020 6 0 6
14642689 2 0 2
20197117 2010 2 0 1
11854117 2002 2 0 2
France Cohort 2020 9 2 7
8877771 1996 5 2 3
10973849 2000 1 0 1
15120823 2004 2 0
16379539 2005 1 0 1
15840476 2005 1 0 1
18808722 2008 1 0 1
26496715 2015 4 0 4
29622001 2018 1 0 1
Literature, cohort, and gnomAD – 28 3 25 –
Variant features alone – 10 7 3 –

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

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
15120823 HEK293 0 None None None None
21367833 hiPSC-CM None None None None

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
15120823 HEK293 None None None
21367833 hiPSC-CM None None None

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 A561T.
Neighbour residue Distance (Å) Observed variants
561 0 A561T, A561P, A561V,
560 4 I560fsX, I560M,
564 5 L564L,
558 5 A558P, A558E, A558V,
562 5 H562P, H562R, H562Q, H562Q,
618 5 T618S, T618S,
619 6
565 6
615 6 L615V, L615F,
559 6 L559F, L559H,
563 6 W563G, W563C, W563C, W563X,
557 7
622 7 L622F,
566 8 C566S, C566R, C566G, C566S, C566F,
614 9 A614T, A614V,
556 9
567 9 I567T, I567M,
644 9 V644I, V644F,
617 9 F617L, F617V, F617L, F617L,
611 9 Y611D,
621 10 S621R, S621N, S621R, S621R,
620 10 S620G, S620I,
642 10 I642V, I642Del,
423 10
623 10 T623I,
647 10
555 11
651 11 M651K,
568 11 W568C, W568C,
648 11 G648A,
646 11
422 11 A422T,
640 11 F640L, F640V, F640Del, F640L, F640L,
426 11 P426H,
616 11 Y616S,
645 11 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
612 11 V612L, V612L, V612A,
554 12
613 12 T613A, T613L, T613K, T613M,
643 12
427 13 Y427H, Y427S, Y427C,
641 13 S641P, S641F,
655 13
652 13 Y652X,
419 13
569 13 Y569H, Y569C, Y569X,
649 13
645 14 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
641 14 S641P, S641F,
553 14 L553V,
639 14 I639F, I639N,
431 14 F431L, F431L, F431L,
624 14 S624R, S624N, S624R, S624R,
643 14
570 14
656 14 F656L, F656L, F656L
424 14
425 14
430 14
638 14 K638E, K638D, K638Del, K638R,
649 14
625 14 V625E,
529 14
650 14 L650X,
571 15 I571L, I571V,
630 15 V630I, V630T, V630A,
646 15
552 15 L552S,
421 15 T421fsX, T421M,