KCNH2 Variant P596S
Summary of observed carriers, functional annotations, and structural context for KCNH2 P596S. Data combine curated literature, international cohorts, and gnomAD observations.
Estimated LQT2 penetrance
44%
90% CI: 26.5% – 70.6%
6/13 effective observations
Total carriers
3
3 LQT2 · 0 unaffected
Functional studies
0
Publications with functional data
We have tested the trafficking efficiency of this variant: 24% 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 3 individuals with LQT2 and 7 unaffected individuals.
In silico predictors
| PROVEAN | PolyPhen-2 | BLAST-PSSM | REVEL | Penetrance Density LQT2 (%) |
|---|---|---|---|---|
| -2.764 | 0.236 | -1 | 0.746 | 92 |
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 |
|---|---|---|---|---|---|
| France Cohort | 2020 | 1 | 0 | 1 | |
| 26496715 | 2015 | 2 | 0 | 2 | |
| Literature, cohort, and gnomAD | – | 3 | 0 | 3 | – |
| 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.
| Neighbour residue | Distance (Å) | Observed variants |
|---|---|---|
| 596 | 0 | P596T, P596S, P596R, P596L, |
| 597 | 5 | Y597H, Y597C, |
| 590 | 5 | G590D, G590V, |
| 595 | 5 | K595E, K595N, K595N, |
| 594 | 6 | |
| 604 | 6 | G604S, G604C, G604D, |
| 591 | 7 | D591N, D591H, |
| 603 | 7 | G603D, |
| 605 | 8 | P605L, |
| 593 | 8 | I593V, I593K, I593T, I593R, I593X, |
| 587 | 9 | |
| 589 | 9 | L589P, |
| 592 | 11 | Q592X, |
| 586 | 11 | L586M, |
| 588 | 11 | N588D, N588K, N588K, |
| 606 | 12 | S606Del, S606P, S606F, |
| 610 | 13 | |
| 584 | 13 | G584S, G584R, G584C, |
| 583 | 14 | I583V, |
| 609 | 14 | D609N, D609G |
| 583 | 14 | I583V, |
| 576 | 14 | |
| 585 | 14 | W585C, W585C, |