KCNH2 Variant G604D

Summary of observed carriers, functional annotations, and structural context for KCNH2 G604D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

36%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

G604D 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 17%. 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 (%)
-6.241 0.999 -2 0.956 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 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.

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 G604D.
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,