KCNH2 Variant P596R

Summary of observed carriers, functional annotations, and structural context for KCNH2 P596R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

35%

90% CI: 18.3% – 65.1%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

1

Publications with functional data

P596R 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 9%. 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 (%)
-1.886 0.096 2 0.63 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

Observed carriers by publication or cohort.
Source Year Carriers Unaffected LQT2 Other Disease
15840476 2005 1 0 1
Literature, cohort, and gnomAD – 1 0 1 –
Variant features alone – 10 7 3 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
16432067 HEK293 10 None None None None

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
16432067 HEK293 None None None

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 P596R.
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,