KCNH2 Variant T634I

Summary of observed carriers, functional annotations, and structural context for KCNH2 T634I. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

35%

90% CI: 21.2% – 64.8%

5/13 effective observations

Total carriers

3

2 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

T634I 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 17%. 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 (%)
-5.801 1.0 -1 0.955 91

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
Italy Cohort 2020 3 1 2
Literature, cohort, and gnomAD – 3 1 2 –
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 T634I.
Neighbour residue Distance (Å) Observed variants
634 0 T634P, T634A, T634S, T634S, T634I,
637 4 E637K, E637G, E637X,
635 4 N635I,
633 5 N633D, N633S, N633I,
636 5
638 6 K638E, K638D, K638Del, K638R,
632 6 P632A, P632S,
584 6 G584S, G584R, G584C,
583 8 I583V,
593 8 I593V, I593K, I593T, I593R, I593X,
575 8 E575K,
571 8 I571L, I571V,
639 9 I639F, I639N,
609 9 D609N, D609G,
631 9 S631F,
585 9 W585C, W585C,
612 9 V612L, V612L, V612A,
572 9 G572S, G572R, G572C, G572D,
592 10 Q592X,
613 10 T613A, T613L, T613K, T613M,
568 10 W568C, W568C,
616 10 Y616S,
629 10 N629D, N629T, N629S, N629I, N629K, N629K,
640 10 F640L, F640V, F640Del, F640L, F640L,
641 10 S641P, S641F,
608 11
589 11 L589P,
577 11
594 11
586 11 L586M,
588 11 N588D, N588K, N588K,
587 11
606 12 S606Del, S606P, S606F,
576 12
595 12 K595E, K595N, K595N,
642 12 I642V, I642Del,
630 12 V630I, V630T, V630A,
570 12
627 13 F627L, F627fsX, F627X, F627L, F627L,
630 13 V630I, V630T, V630A,
573 13
590 13 G590D, G590V,
617 13 F617L, F617V, F617L, F617L,
610 13
605 13 P605L,
574 13 M574L, M574V, M574L,
614 13 A614T, A614V,
615 14 L615V, L615F,
628 14 G628S, G628R, G628Del, G628D, G628A, G628V,
611 14 Y611D,
567 14 I567T, I567M,
569 14 Y569H, Y569C, Y569X,
643 14
591 14 D591N, D591H,
607 14
588 15 N588D, N588K, N588K,
589 15 L589P,
644 15 V644I, V644F
628 15 G628S, G628R, G628Del, G628D, G628A, G628V,