KCNH2 Variant E544A

Summary of observed carriers, functional annotations, and structural context for KCNH2 E544A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

40%

90% CI: 18.3% – 62.9%

4/12 effective observations

Total carriers

2

2 LQT2 · 0 unaffected

Functional studies

3

Publications with functional data

E544A has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 65% 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.746 1.0 -1 0.934 76

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

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
9882738 Xeno 211 None None None 0.291666667
15528201 Xeno -4.7 14.3 None None
27317659 HEK293 -1.8 None None 0.397274633

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
9882738 Xeno None None None
15528201 Xeno None None None
27317659 HEK293 None None None

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 E544A.
Neighbour residue Distance (Å) Observed variants
544 0 E544A, E544fsX,
545 5
543 5 S543fsX,
541 7 R541C, R541H,
540 7 D540fsX,
3 7
681 8 R681W,
542 8
546 8
548 9
674 9 H674Y, H674fsX,
677 9 M677T,
549 10 V549M,
539 10
412 10 W412X,
678 10
547 10 A547T,
408 10
673 11
698 11 E698K, E698X
411 12
538 12
665 12 R665Q,
4 12
702 12
685 12 R685C, R685H, R685P,
680 13
409 13 V409M, V409L, V409L,
552 13 L552S,
5 13
694 13 R694C, R694H,
675 13
682 13 E682X,
666 13
403 13
405 13
402 13 H402R,
662 14
670 14
535 14 V535M,
550 14
407 14
404 14
684 14
551 14 F551L, F551L, F551L,
701 14
415 14
671 14 A671G, A671Del,
536 14 A536X,
676 15 Q676fsX, Q676X,