KCNH2 Variant E438D

Summary of observed carriers, functional annotations, and structural context for KCNH2 E438D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

8%

0/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

E438D has not been reported in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 62% of WT with a standard error of 20%. 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 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-0.953 0.023 2 0.584 4

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 – 0 0 0 –
Variant features alone – 10 10 0 –

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 E438D.
Neighbour residue Distance (Å) Observed variants
438 0 E438K, E438X,
437 4
439 4
436 5 T436M,
440 5 P440L,
435 7 E435G, E435X,
441 7 P441R, P441L,
434 8
442 8
433 8
443 8 T443fsX, T443N,
432 9
444 9 E444K, E444D, E444D,
431 10 F431L, F431L, F431L,
445 10
430 11
446 11
429 11 A429P, A429V,
447 11 Y447X,
428 12 S428fsX, S428X, S428L,
448 12 A448T, A448S,
427 13 Y427H, Y427S, Y427C,
449 13
426 13 P426H,
450 13
425 14
451 14 P451L
424 14
452 14
423 15
453 15