KCNH2 Variant I583V
Summary of observed carriers, functional annotations, and structural context for KCNH2 I583V. Data combine curated literature, international cohorts, and gnomAD observations.
Estimated LQT2 penetrance
15%
90% CI: 3.6% – 28.4%
2/20 effective observations
Total carriers
10
1 LQT2 · 8 unaffected
Functional studies
0
Publications with functional data
We have tested the trafficking efficiency of this variant: 101% of WT with a standard error of 25%. 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 1 individuals with LQT2 and 9 unaffected individuals.
In silico predictors
| PROVEAN | PolyPhen-2 | BLAST-PSSM | REVEL | Penetrance Density LQT2 (%) |
|---|---|---|---|---|
| -0.823 | 0.236 | 3 | 0.725 | 44 |
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 |
|---|---|---|---|---|---|
| Italy Cohort | 2020 | 9 | 8 | 1 | |
| Literature, cohort, and gnomAD | – | 10 | 8 | 1 | – |
| Variant features alone | – | 10 | 9 | 1 | – |
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 |
|---|---|---|
| 583 | 0 | I583V, |
| 584 | 4 | G584S, G584R, G584C, |
| 587 | 6 | |
| 633 | 7 | N633D, N633S, N633I, |
| 634 | 8 | T634P, T634A, T634S, T634S, T634I, |
| 577 | 8 | |
| 593 | 8 | I593V, I593K, I593T, I593R, I593X, |
| 588 | 8 | N588D, N588K, N588K, |
| 594 | 8 | |
| 576 | 9 | |
| 592 | 9 | Q592X, |
| 586 | 9 | L586M, |
| 585 | 10 | W585C, W585C, |
| 637 | 10 | E637K, E637G, E637X, |
| 575 | 10 | E575K, |
| 572 | 10 | G572S, G572R, G572C, G572D, |
| 595 | 11 | K595E, K595N, K595N, |
| 635 | 11 | N635I, |
| 591 | 11 | D591N, D591H, |
| 632 | 11 | P632A, P632S, |
| 597 | 11 | Y597H, Y597C, |
| 631 | 11 | S631F, |
| 636 | 12 | |
| 590 | 12 | G590D, G590V, |
| 589 | 12 | L589P, |
| 590 | 12 | G590D, G590V, |
| 591 | 12 | D591N, D591H, |
| 571 | 12 | I571L, I571V, |
| 589 | 12 | L589P, |
| 638 | 13 | K638E, K638D, K638Del, K638R |
| 573 | 13 | |
| 629 | 13 | N629D, N629T, N629S, N629I, N629K, N629K, |
| 568 | 14 | W568C, W568C, |
| 630 | 14 | V630I, V630T, V630A, |
| 596 | 14 | P596T, P596S, P596R, P596L, |
| 592 | 14 | Q592X, |
| 609 | 14 | D609N, D609G, |
| 596 | 14 | P596T, P596S, P596R, P596L, |
| 605 | 15 | P605L, |
| 606 | 15 | S606Del, S606P, S606F, |
| 574 | 15 | M574L, M574V, M574L, |
| 588 | 15 | N588D, N588K, N588K, |
| 570 | 15 |