KCNH2 Variant Y427H

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y427H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

40%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y427H has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 1%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-4.692 0.997 2 0.984 58

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
16922724 2006 1 0 1
Literature, cohort, and gnomAD – 1 0 1 –
Variant features alone – 10 7 3 –

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 Y427H.
Neighbour residue Distance (Å) Observed variants
427 0 Y427H, Y427S, Y427C,
428 5 S428fsX, S428X, S428L,
431 5 F431L, F431L, F431L,
424 6
426 6 P426H,
611 7 Y611D,
430 7
429 7 A429P, A429V,
423 7
432 8
566 8 C566S, C566R, C566G, C566S, C566F,
425 8
562 8 H562P, H562R, H562Q, H562Q,
607 8
569 10 Y569H, Y569C, Y569X,
452 10
565 10
608 10
610 10
422 10 A422T,
420 11 Y420C,
612 11 V612L, V612L, V612A,
563 11 W563G, W563C, W563C, W563X,
615 12 L615V, L615F
609 12 D609N, D609G,
614 12 A614T, A614V,
421 12 T421fsX, T421M,
525 12 K525N, K525N,
567 12 I567T, I567M,
570 12
606 12 S606Del, S606P, S606F,
456 12 D456Y,
559 13 L559F, L559H,
561 13 A561T, A561P, A561V,
453 13
522 13 G522E,
526 13
528 13 R528W, R528X, R528P,
564 13 L564L,
613 13 T613A, T613L, T613K, T613M,
419 14
573 14
558 14 A558P, A558E, A558V,
450 14
529 14
451 14 P451L,
455 14
523 14
568 15 W568C, W568C,