KCNH2 Variant E575K

Summary of observed carriers, functional annotations, and structural context for KCNH2 E575K. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

39%

90% CI: 17.3% – 63.7%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

E575K has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 24% of WT with a standard error of 13%. 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 (%)
-3.791 0.887 1 0.955 88

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
26496715 2015 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 E575K.
Neighbour residue Distance (Å) Observed variants
575 0 E575K,
572 6 G572S, G572R, G572C, G572D,
574 6 M574L, M574V, M574L,
576 6
571 6 I571L, I571V,
577 7
636 7
573 7
634 8 T634P, T634A, T634S, T634S, T634I,
570 8
637 9 E637K, E637G, E637X,
584 10 G584S, G584R, G584C,
635 10 N635I,
583 10 I583V,
585 11 W585C, W585C,
586 11 L586M,
569 11 Y569H, Y569C, Y569X,
568 11 W568C, W568C,
587 11
633 12 N633D, N633S, N633I,
639 12 I639F, I639N,
567 13 I567T, I567M,
638 13 K638E, K638D, K638Del, K638R,
640 13 F640L, F640V, F640Del, F640L, F640L
632 13 P632A, P632S,
593 14 I593V, I593K, I593T, I593R, I593X,
608 14
430 15
609 15 D609N, D609G,
597 15 Y597H, Y597C,