KCNH2 Variant A558T

Summary of observed carriers, functional annotations, and structural context for KCNH2 A558T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

26%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A558T has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 129% of WT with a standard error of 15%. 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 (%)
-3.6 0.616 0 0.923 67

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
Literature, cohort, and gnomAD – 0 0 0 –
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 A558T.
Neighbour residue Distance (Å) Observed variants
558 0 A558P, A558V, A558E,
559 4 L559F, L559H,
557 5
561 5 A561V, A561P, A561T,
560 5 I560fsX, I560M
556 6
555 6
562 6 H562P, H562Q, H562R, H562Q,
619 7
554 7
563 8 W563C, W563G, W563X, W563C,
615 8 L615V, L615F,
646 8
423 9
618 9 T618S, T618S,
564 10 L564L,
422 10 A422T,
622 10 L622F,
419 10
642 10 I642Del, I642V,
553 10 L553V,
565 10
552 11 L552S,
551 11 F551L, F551L, F551L,
651 11 M651K,
655 11
611 11 Y611D,
645 11 M645I, M645I, M645I, M645L, M645V, M645R, M645L,
566 12 C566G, C566R, C566S, C566S, C566F,
623 12 T623I,
649 12
643 12
656 12 F656L, F656L, F656L,
614 12 A614V, A614T,
426 13 P426H,
620 13 S620I, S620G,
648 13 G648A,
550 13
652 13 Y652X,
424 13
612 13 V612L, V612A, V612L,
647 13
621 13 S621R, S621R, S621N, S621R,
650 13 L650X,
647 13
644 13 V644F, V644I,
639 13 I639F, I639N,
421 14 T421M, T421fsX,
418 14
617 14 F617L, F617V, F617L, F617L,
532 14
567 14 I567T, I567M,
616 14 Y616S,
427 14 Y427S, Y427H, Y427C,
641 14 S641P, S641F,
648 14 G648A,
644 14 V644F, V644I,
415 14
420 14 Y420C,
425 14
416 15
529 15
659 15
654 15