KCNH2 Variant D591H

Summary of observed carriers, functional annotations, and structural context for KCNH2 D591H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

90% CI: 1.7% – 32.7%

1/13 effective observations

Total carriers

3

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

D591H is present in 3 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 51% of WT with a standard error of 15%. 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-3.221 0.633 -1 0.765 31

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
Literature, cohort, and gnomAD – 3 1 0 –
Variant features alone – 10 9 1 –

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 D591H.
Neighbour residue Distance (Å) Observed variants
591 0 D591N, D591H,
590 4 G590D, G590V,
592 5 Q592X,
588 5 N588D, N588K, N588K,
589 6 L589P,
596 7 P596T, P596S, P596R, P596L,
593 7 I593V, I593K, I593T, I593R, I593X,
594 7
587 8
595 8 K595E, K595N, K595N,
597 9 Y597H, Y597C,
586 10 L586M,
584 10 G584S, G584R, G584C,
605 11 P605L,
583 11 I583V,
633 11 N633D, N633S, N633I,
604 11 G604S, G604C, G604D,
585 11 W585C, W585C,
629 12 N629D, N629T, N629S, N629I, N629K, N629K,
583 12 I583V,
630 12 V630I, V630T, V630A,
631 13 S631F,
603 13 G603D,
633 13 N633D, N633S, N633I,
613 14 T613A, T613L, T613K, T613M,
628 14 G628S, G628R, G628Del, G628D, G628A, G628V,
584 14 G584S, G584R, G584C,
610 14
606 14 S606Del, S606P, S606F,
609 14 D609N, D609G,
592 14 Q592X,
588 14 N588D, N588K, N588K,
634 14 T634P, T634A, T634S, T634S, T634I
631 15 S631F,
632 15 P632A, P632S,