KCNH2 Variant D501E

Summary of observed carriers, functional annotations, and structural context for KCNH2 D501E. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

31%

3/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

D501E has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 22% of WT with a standard error of 9%. 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 (%)
-3.707 0.997 1 0.881 78

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 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 D501E.
Neighbour residue Distance (Å) Observed variants
501 0 D501Y, D501H, D501N,
500 5 I500Del,
502 5 M502I, M502I, M502I,
534 5 R534C,
498 6
504 6 A504V,
503 7
499 7
467 7
530 7
497 7 W497L, W497X,
533 7
531 8 R531Q, R531W, R531Del,
505 8 A505V,
493 8 Y493H, Y493F, Y493C, Y493Ins,
463 8 F463L, F463L, F463L,
466 8 D466E, D466E,
537 8 R537W,
496 9
470 9 N470D,
464 10 I464X,
532 10
506 10 I506V,
527 10
538 11
494 11 F494Del,
535 11 V535M,
471 11 F471X,
536 12 A536X,
529 12
414 12 I414fsX,
465 12
468 12 L468F, L468R, L468X,
528 12 R528X, R528W, R528P,
418 12
469 12
460 13 D460fsX,
462 13 M462Ins,
495 13 K495X,
492 13 H492Y,
421 13 T421fsX, T421M,
417 13
507 13 P507L, P507S,
459 14
411 14
490 14 A490T, A490P,
461 14
410 14 W410X,
473 14 T473P,
526 14
415 15