KCNH2 Variant G584R

Summary of observed carriers, functional annotations, and structural context for KCNH2 G584R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

21%

2/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

G584R 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 4%. 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 (%)
-7.549 1.0 -3 0.978 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
29497013 2018 1 1
Literature, cohort, and gnomAD – 1 1 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 G584R.
Neighbour residue Distance (Å) Observed variants
584 0 G584S, G584R, G584C,
583 4 I583V,
587 5
633 6 N633D, N633S, N633I,
588 6 N588D, N588K, N588K,
585 6 W585C, W585C,
586 6 L586M,
634 6 T634P, T634A, T634S, T634S, T634I,
637 7 E637K, E637G, E637X,
572 8 G572S, G572R, G572C, G572D,
631 8 S631F,
632 8 P632A, P632S,
589 9 L589P,
576 9
593 9 I593V, I593K, I593T, I593R, I593X,
592 10 Q592X,
575 10 E575K,
577 10
571 10 I571L, I571V,
630 10 V630I, V630T, V630A,
590 10 G590D, G590V,
568 10 W568C, W568C,
636 10
591 10 D591N, D591H,
635 11 N635I,
638 11 K638E, K638D, K638Del, K638R,
629 11 N629D, N629T, N629S, N629I, N629K, N629K,
573 11
597 11 Y597H, Y597C,
592 11 Q592X,
594 12
569 12 Y569H, Y569C, Y569X,
570 13
613 13 T613A, T613L, T613K, T613M,
617 13 F617L, F617V, F617L, F617L,
610 13
629 13 N629D, N629T, N629S, N629I, N629K, N629K,
628 13 G628S, G628R, G628Del, G628D, G628A, G628V,
589 13 L589P,
605 13 P605L,
614 13 A614T, A614V,
596 13 P596T, P596S, P596R, P596L,
640 14 F640L, F640V, F640Del, F640L, F640L,
591 14 D591N, D591H,
574 14 M574L, M574V, M574L,
595 14 K595E, K595N, K595N,
590 14 G590D, G590V,
593 14 I593V, I593K, I593T, I593R, I593X,
628 14 G628S, G628R, G628Del, G628D, G628A, G628V,
641 14 S641P, S641F
616 14 Y616S,
627 14 F627L, F627fsX, F627X, F627L, F627L,
639 14 I639F, I639N,
609 15 D609N, D609G,
613 15 T613A, T613L, T613K, T613M,
604 15 G604S, G604C, G604D,