KCNH2 Variant A614T

Summary of observed carriers, functional annotations, and structural context for KCNH2 A614T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

34%

90% CI: 34.9% – 75.9%

8/15 effective observations

Total carriers

5

5 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A614T 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 29%. 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 (%)
-3.791 0.998 0 0.933 87

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
Italy Cohort 2020 2 0 2
Literature, cohort, and gnomAD – 5 0 5 –
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 A614T.
Neighbour residue Distance (Å) Observed variants
614 0 A614T, A614V,
613 4 T613A, T613L, T613K, T613M,
615 4 L615V, L615F,
565 5
612 6 V612L, V612L, V612A,
617 6 F617L, F617V, F617L, F617L,
611 6 Y611D,
568 6 W568C, W568C,
618 6 T618S, T618S,
616 7 Y616S,
566 8 C566S, C566R, C566G, C566S, C566F,
585 8 W585C, W585C,
610 8
569 8 Y569H, Y569C, Y569X,
609 8 D609N, D609G,
630 8 V630I, V630T, V630A,
564 8 L564L,
561 9 A561T, A561P, A561V,
638 9 K638E, K638D, K638Del, K638R,
619 9
562 9 H562P, H562R, H562Q, H562Q,
567 9 I567T, I567M,
620 10 S620G, S620I,
642 10 I642V, I642Del,
586 10 L586M,
431 10 F431L, F431L, F431L,
589 10 L589P,
570 10
621 11 S621R, S621N, S621R, S621R,
640 11 F640L, F640V, F640Del, F640L, F640L,
571 11 I571L, I571V,
607 11
631 11 S631F,
608 11
635 11 N635I,
639 11 I639F, I639N,
572 11 G572S, G572R, G572C, G572D,
629 11 N629D, N629T, N629S, N629I, N629K, N629K,
637 12 E637K, E637G, E637X,
427 12 Y427H, Y427S, Y427C,
622 12 L622F,
641 12 S641P, S641F,
430 12
632 12 P632A, P632S,
606 12 S606Del, S606P, S606F,
644 12 V644I, V644F,
632 12 P632A, P632S,
627 12 F627L, F627fsX, F627X, F627L, F627L,
558 12 A558P, A558E, A558V,
563 12 W563G, W563C, W563C, W563X,
641 12 S641P, S641F,
573 12
645 12 M645L, M645V, M645L, M645R, M645I, M645I, M645I
628 13 G628S, G628R, G628Del, G628D, G628A, G628V,
560 13 I560fsX, I560M,
605 13 P605L,
588 13 N588D, N588K, N588K,
633 13 N633D, N633S, N633I,
426 13 P426H,
626 13 G626S, G626A, G626V,
634 13 T634P, T634A, T634S, T634S, T634I,
592 13 Q592X,
584 13 G584S, G584R, G584C,
559 14 L559F, L559H,
623 14 T623I,
627 14 F627L, F627fsX, F627X, F627L, F627L,
593 14 I593V, I593K, I593T, I593R, I593X,
625 14 V625E,
423 14
636 14
637 14 E637K, E637G, E637X,
557 14
590 14 G590D, G590V,
636 15
631 15 S631F,
633 15 N633D, N633S, N633I,
587 15
429 15 A429P, A429V,
646 15
643 15