KCNH2 Variant F406Y

Summary of observed carriers, functional annotations, and structural context for KCNH2 F406Y. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

15%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F406Y has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 142% of WT with a standard error of 19%. 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 (%)
-2.853 0.63 3 0.884 26

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 F406Y.
Neighbour residue Distance (Å) Observed variants
406 0
407 5
405 6
404 6
410 6 W410X,
409 7 V409M, V409L, V409L,
408 7
400 8 I400N,
401 9
469 9
411 9
473 10 T473P,
413 10 L413P,
403 11
402 11 H402R,
466 11 D466E, D466E,
399 12
414 12 I414fsX,
465 12
541 12 R541H, R541C,
412 12 W412X,
470 12 N470D,
474 12 T474I,
462 12 M462Ins,
472 13 R472C, R472X,
398 13 W398L, W398X,
468 13 L468F, L468X, L468R,
538 14