KCNH2 Variant E365D

Summary of observed carriers, functional annotations, and structural context for KCNH2 E365D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

19%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

E365D has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 124% of WT with a standard error of 14%. 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 (%)
0.095 0.003 5 0.548 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
Literature, cohort, and gnomAD – 0 0 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 E365D.
Neighbour residue Distance (Å) Observed variants
365 0 E365G,
364 4 K364X,
366 4 R366X, R366Q,
363 5 I363X,
367 5 T367S, T367S,
362 7
368 7 H368Y,
361 8
369 8 N369K, N369K,
360 8
370 8
359 9 I359V,
371 9
358 10
372 10
357 11 E357D, E357D,
373 11
356 11 R356C, R356H,
374 11
355 12 D355G,
375 12
354 13
376 13 Q376sp, Q376R,
353 13 T353S, T353S,
377 13
352 14
378 14
351 14 S351L,
379 14 S379Y,
350 15
380 15 L380X