KCNH2 Variant G590V

Summary of observed carriers, functional annotations, and structural context for KCNH2 G590V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

23%

90% CI: 4.0% – 36.6%

2/13 effective observations

Total carriers

3

0 LQT2 · 3 unaffected

Functional studies

0

Publications with functional data

G590V has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 38% of WT with a standard error of 10%. 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-6.727 0.88 -3 0.851 58

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 3 3 0
Literature, cohort, and gnomAD – 3 3 0 –
Variant features alone – 10 8 2 –

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 G590V.
Neighbour residue Distance (Å) Observed variants
590 0 G590D, G590V,
591 4 D591N, D591H,
589 4 L589P,
593 5 I593V, I593K, I593T, I593R, I593X,
596 5 P596T, P596S, P596R, P596L,
595 6 K595E, K595N, K595N,
592 6 Q592X,
594 6
588 6 N588D, N588K, N588K,
587 7
597 7 Y597H, Y597C,
605 7 P605L,
586 7 L586M,
604 8 G604S, G604C, G604D,
585 10 W585C, W585C,
584 10 G584S, G584R, G584C,
603 10 G603D,
610 10
606 11 S606Del, S606P, S606F,
633 11 N633D, N633S, N633I,
609 11 D609N, D609G,
613 12 T613A, T613L, T613K, T613M,
583 12 I583V,
583 12 I583V,
629 12 N629D, N629T, N629S, N629I, N629K, N629K,
630 12 V630I, V630T, V630A,
634 13 T634P, T634A, T634S, T634S, T634I,
631 13 S631F,
635 13 N635I,
572 13 G572S, G572R, G572C, G572D,
576 14
607 14
584 14 G584S, G584R, G584C,
638 14 K638E, K638D, K638Del, K638R
569 14 Y569H, Y569C, Y569X,
633 14 N633D, N633S, N633I,
573 14
612 14 V612L, V612L, V612A,
628 14 G628S, G628R, G628Del, G628D, G628A, G628V,
614 14 A614T, A614V,
632 15 P632A, P632S,