KCNH2 Variant Y403N

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y403N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

17%

90% CI: 2.8% – 38.9%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y403N has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 125% of WT with a standard error of 17%. 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 (%)
-8.55 0.866 -2 0.94 73

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 Y403N.
Neighbour residue Distance (Å) Observed variants
403 0
402 5 H402R,
404 5
401 5
5 6
405 8
474 8 T474I,
3 9
6 9 G6R,
407 9
400 10 I400N,
408 10
482 10 V482A,
695 10
541 10 R541C, R541H,
476 11 V476I,
473 11 T473P,
4 11
406 11
8 11
7 11
481 12
698 12 E698K, E698X,
691 12
483 12 V483I,
399 12
475 12 Y475C, Y475Del,
694 12 R694C, R694H,
484 12
699 13 E699D, E699D,
409 13 V409M, V409L, V409L,
411 13
544 13 E544A, E544fsX,
540 14 D540fsX,
692 14
702 14
538 15
480 15 E480V,
9 15 A9T, A9V
469 15
410 15 W410X,
470 15 N470D,