KCNH2 Variant T556A

Summary of observed carriers, functional annotations, and structural context for KCNH2 T556A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

20%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

T556A 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 7%. 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 (%)
-3.974 0.236 0 0.791 61

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 T556A.
Neighbour residue Distance (Å) Observed variants
556 0
555 4
559 5 L559F, L559H,
558 6 A558P, A558E, A558V,
557 6
553 6 L553V,
560 6 I560fsX, I560M,
552 6 L552S,
554 7
655 8
551 8 F551L, F551L, F551L,
651 9 M651K,
561 9 A561T, A561P, A561V,
563 9 W563G, W563C, W563C, W563X,
419 9
550 10
422 10 A422T,
532 10
562 10 H562P, H562R, H562Q, H562Q,
656 10 F656L, F656L, F656L,
549 11 V549M,
535 11 V535M,
423 11
415 11
646 11
619 12
654 12
418 12
622 12 L622F,
659 12
548 12
658 12
564 12 L564L,
647 13
648 13 G648A,
652 13 Y652X,
536 13 A536X,
539 13
542 13
649 13
618 13 T618S, T618S,
421 13 T421fsX, T421M,
650 13 L650X,
650 13 L650X,
529 14
416 14
653 14
615 14 L615V, L615F,
657 14 G657S, G657V
623 14 T623I,
533 14
547 14 A547T,
565 14
543 14 S543fsX,
662 15
426 15 P426H,
642 15 I642V, I642Del,
644 15 V644I, V644F,