KCNH2 Variant I593K
Summary of observed carriers, functional annotations, and structural context for KCNH2 I593K. Data combine curated literature, international cohorts, and gnomAD observations.
Estimated LQT2 penetrance
19%
90% CI: 4.0% – 40.4%
2/11 effective observations
Total carriers
1
0 LQT2 · 1 unaffected
Functional studies
0
Publications with functional data
We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 22%. 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
| PROVEAN | PolyPhen-2 | BLAST-PSSM | REVEL | Penetrance Density LQT2 (%) |
|---|---|---|---|---|
| -5.156 | 0.941 | -3 | 0.94 | 55 |
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
| Source | Year | Carriers | Unaffected | LQT2 | Other Disease |
|---|---|---|---|---|---|
| Literature, cohort, and gnomAD | – | 1 | 1 | 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.
| Neighbour residue | Distance (Å) | Observed variants |
|---|---|---|
| 593 | 0 | I593V, I593K, I593T, I593R, I593X, |
| 594 | 4 | |
| 592 | 5 | Q592X, |
| 595 | 5 | K595E, K595N, K595N, |
| 590 | 5 | G590D, G590V, |
| 589 | 5 | L589P, |
| 633 | 7 | N633D, N633S, N633I, |
| 591 | 7 | D591N, D591H, |
| 583 | 8 | I583V, |
| 605 | 8 | P605L, |
| 634 | 8 | T634P, T634A, T634S, T634S, T634I, |
| 596 | 8 | P596T, P596S, P596R, P596L, |
| 609 | 9 | D609N, D609G, |
| 606 | 9 | S606Del, S606P, S606F, |
| 635 | 9 | N635I, |
| 588 | 9 | N588D, N588K, N588K, |
| 604 | 9 | G604S, G604C, G604D, |
| 584 | 9 | G584S, G584R, G584C, |
| 613 | 10 | T613A, T613L, T613K, T613M, |
| 586 | 10 | L586M, |
| 610 | 10 | |
| 629 | 11 | N629D, N629T, N629S, N629I, N629K, N629K, |
| 638 | 11 | K638E, K638D, K638Del, K638R, |
| 632 | 11 | P632A, P632S, |
| 597 | 11 | Y597H, Y597C, |
| 637 | 11 | E637K, E637G, E637X, |
| 587 | 12 | |
| 612 | 12 | V612L, V612L, V612A, |
| 585 | 12 | W585C, W585C, |
| 630 | 12 | V630I, V630T, V630A, |
| 608 | 12 | |
| 631 | 12 | S631F, |
| 636 | 12 | |
| 603 | 13 | G603D, |
| 607 | 13 | |
| 588 | 13 | N588D, N588K, N588K, |
| 577 | 13 | |
| 616 | 13 | Y616S, |
| 587 | 13 | |
| 614 | 14 | A614T, A614V, |
| 628 | 14 | G628S, G628R, G628Del, G628D, G628A, G628V, |
| 584 | 14 | G584S, G584R, G584C, |
| 575 | 14 | E575K, |
| 631 | 15 | S631F, |
| 585 | 15 | W585C, W585C, |
| 639 | 15 | I639F, I639N |