KCNH2 Variant G604S

Summary of observed carriers, functional annotations, and structural context for KCNH2 G604S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

72%

90% CI: 69.2% – 87.9%

39/50 effective observations

Total carriers

40

36 LQT2 · 4 unaffected

Functional studies

1

Publications with functional data

G604S 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 (%)
-3.85 1.0 0 0.958 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
Japan Cohort 2020 6 2 4
24103226 2014 1 0 1 Seizures
Italy Cohort 2020 5 0 5
11854117 2002 2 0 2
France Cohort 2020 9 1 8
10220144 1999 1 0 1
10973849 2000 1 0 1
14998624 2004 1 0 1
15840476 2005 4 0 4
17171344 2007 10 1 9
22402334 2012 1 0 1
22821100 2012 None 0 1
26496715 2015 2 0 2
Literature, cohort, and gnomAD – 40 4 36 –
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)
18386051 HEK293 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)
18386051 HEK293 31 -0.3 -9.3 1.0

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 G604S.
Neighbour residue Distance (Å) Observed variants
604 0 G604S, G604C, G604D,
605 3 P605L,
603 3 G603D,
595 5 K595E, K595N, K595N,
597 6 Y597H, Y597C,
596 6 P596T, P596S, P596R, P596L,
606 7 S606Del, S606P, S606F,
590 8 G590D, G590V,
594 8
610 9
593 9 I593V, I593K, I593T, I593R, I593X,
607 9
589 10 L589P,
586 10 L586M,
609 10 D609N, D609G,
587 10
591 11 D591N, D591H,
608 13
573 13
592 13 Q592X,
569 13 Y569H, Y569C, Y569X,
588 13 N588D, N588K, N588K,
576 13
585 13 W585C, W585C,
613 14 T613A, T613L, T613K, T613M,
431 14 F431L, F431L, F431L,
572 14 G572S, G572R, G572C, G572D,
635 14 N635I
584 15 G584S, G584R, G584C,
612 15 V612L, V612L, V612A,