KCNH2 Variant I414N

Summary of observed carriers, functional annotations, and structural context for KCNH2 I414N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

22%

90% CI: 4.9% – 45.0%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I414N has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 84% of WT with a standard error of 24%. 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 (%)
-6.653 1.0 -4 0.925 70

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 I414N.
Neighbour residue Distance (Å) Observed variants
414 0 I414fsX,
413 5 L413P,
417 5
415 5
411 5
410 6 W410X,
418 6
416 7
534 7 R534C,
463 7 F463L, F463L, F463L,
466 8 D466E, D466E,
462 8 M462Ins,
412 8 W412X,
535 8 V535M,
538 8
542 9
409 9 V409M, V409L, V409L,
407 9
531 9 R531W, R531Del, R531Q,
419 9
459 10
408 10
532 10
421 10 T421fsX, T421M,
465 10
541 11 R541C, R541H,
537 11 R537W,
469 11
533 11
420 11 Y420C,
470 11 N470D,
406 12
501 12 D501N, D501H, D501Y,
536 12 A536X,
467 12
464 12 I464X,
461 12
460 12 D460fsX,
539 13
422 13 A422T,
504 13 A504V,
458 13
552 13 L552S
530 13
528 14 R528W, R528X, R528P,
540 14 D540fsX,
468 14 L468F, L468X, L468R,
505 14 A505V,
529 14
551 14 F551L, F551L, F551L,
473 14 T473P,
555 14
405 15
456 15 D456Y,
404 15
423 15
497 15 W497L, W497X,
455 15
548 15