KCNH2 Variant N588D

Summary of observed carriers, functional annotations, and structural context for KCNH2 N588D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

55%

90% CI: 38.7% – 76.1%

10/18 effective observations

Total carriers

8

8 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

N588D has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 115% of WT with a standard error of 28%. 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 (%)
-3.321 0.265 0 0.622 59

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
9693036 1998 7 0 7
15840476 2005 1 0 1
Literature, cohort, and gnomAD – 8 0 8 –
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 N588D.
Neighbour residue Distance (Å) Observed variants
588 0 N588D, N588K, N588K,
589 5 L589P,
591 5 D591N, D591H,
592 6 Q592X,
584 6 G584S, G584R, G584C,
590 6 G590D, G590V,
587 6
585 7 W585C, W585C,
586 7 L586M,
631 8 S631F,
630 8 V630I, V630T, V630A,
583 8 I583V,
633 9 N633D, N633S, N633I,
629 9 N629D, N629T, N629S, N629I, N629K, N629K,
593 9 I593V, I593K, I593T, I593R, I593X,
628 10 G628S, G628R, G628Del, G628D, G628A, G628V,
632 10 P632A, P632S,
592 11 Q592X,
613 11 T613A, T613L, T613K, T613M,
629 11 N629D, N629T, N629S, N629I, N629K, N629K,
597 11 Y597H, Y597C,
596 11 P596T, P596S, P596R, P596L,
633 11 N633D, N633S, N633I,
637 11 E637K, E637G, E637X,
594 11
634 11 T634P, T634A, T634S, T634S, T634I,
605 11 P605L,
595 12 K595E, K595N, K595N,
572 12 G572S, G572R, G572C, G572D,
568 12 W568C, W568C,
610 12
617 13 F617L, F617V, F617L, F617L,
628 13 G628S, G628R, G628Del, G628D, G628A, G628V,
593 13 I593V, I593K, I593T, I593R, I593X,
614 13 A614T, A614V,
609 13 D609N, D609G,
604 13 G604S, G604C, G604D,
616 13 Y616S,
576 13
632 13 P632A, P632S,
631 13 S631F,
627 14 F627L, F627fsX, F627X, F627L, F627L,
638 14 K638E, K638D, K638Del, K638R
569 14 Y569H, Y569C, Y569X,
571 14 I571L, I571V,
573 14
638 14 K638E, K638D, K638Del, K638R
591 14 D591N, D591H,
606 14 S606Del, S606P, S606F,
627 14 F627L, F627fsX, F627X, F627L, F627L,
577 14
634 15 T634P, T634A, T634S, T634S, T634I,
612 15 V612L, V612L, V612A,
594 15
583 15 I583V,
628 15 G628S, G628R, G628Del, G628D, G628A, G628V,
636 15