KCNH2 Variant I400V

Summary of observed carriers, functional annotations, and structural context for KCNH2 I400V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

22%

90% CI: 5.1% – 45.5%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I400V has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 83% 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-0.752 0.296 3 0.609 79

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 I400V.
Neighbour residue Distance (Å) Observed variants
400 0 I400N,
401 4
399 4
473 5 T473P,
474 7 T474I,
472 7 R472C, R472X,
398 7 W398L, W398X,
469 8
404 8
406 8
407 8
402 9 H402R,
403 10
484 10
470 10 N470D,
485 10 H485X,
405 10
471 11 F471X,
489 11 I489F, I489I,
468 11 L468F, L468X, L468R,
483 11 V483I,
486 11
410 12 W410X,
475 12 Y475C, Y475Del,
408 12
466 12 D466E, D466E,
482 13 V482A,
465 13
411 13
409 14 V409M, V409L, V409L,
467 14
476 14 V476I,
493 14 Y493H, Y493C, Y493F, Y493Ins,
5 14
490 15 A490T, A490P,
541 15 R541C, R541H
487 15 G487S, G487R,
488 15 R488C, R488H,