KCNH2 Variant D466N

Summary of observed carriers, functional annotations, and structural context for KCNH2 D466N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

25%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

D466N has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 15% 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 (%)
-4.633 1.0 1 0.967 62

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 8 2 –

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 D466N.
Neighbour residue Distance (Å) Observed variants
466 0 D466E, D466E,
467 5
465 5
469 5
470 5 N470D,
463 6 F463L, F463L, F463L,
468 7 L468F, L468X, L468R,
534 7 R534C,
462 7 M462Ins,
464 7 I464X,
410 7 W410X,
414 8 I414fsX,
501 8 D501N, D501H, D501Y,
407 9
411 9
471 9 F471X,
473 10 T473P,
531 10 R531W, R531Del, R531Q,
493 10 Y493H, Y493C, Y493F, Y493Ins,
461 10
505 10 A505V,
538 10
504 10 A504V,
417 10
498 10
413 10 L413P,
537 11 R537W,
502 11 M502I, M502I, M502I,
459 11
460 11 D460fsX,
406 11
418 12
472 12 R472C, R472X,
533 12
400 12 I400N,
535 12 V535M,
415 12
497 13 W497L, W497X,
500 13 I500Del,
408 13
409 13 V409M, V409L, V409L,
503 13
474 13 T474I,
532 13
530 13
458 13
416 14
506 14 I506V,
489 14 I489F, I489I,
541 14 R541C, R541H
402 14 H402R,
421 14 T421fsX, T421M,
412 14 W412X,
536 14 A536X,
528 14 R528W, R528X, R528P,
499 14
542 14
496 14
490 15 A490T, A490P,
494 15 F494Del,
404 15
401 15