KCNH2 Variant P426L

Summary of observed carriers, functional annotations, and structural context for KCNH2 P426L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

25%

90% CI: 6.8% – 49.3%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

P426L 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 3%. 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 (%)
-9.517 0.999 -3 0.935 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
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 P426L.
Neighbour residue Distance (Å) Observed variants
426 0 P426H,
425 4
429 5 A429P, A429V,
428 6 S428fsX, S428X, S428L,
566 6 C566S, C566R, C566G, C566S, C566F,
427 6 Y427H, Y427S, Y427C,
423 6
430 6
422 6 A422T,
563 7 W563G, W563C, W563C, W563X,
562 7 H562P, H562R, H562Q, H562Q,
424 7
526 8
431 8 F431L, F431L, F431L,
529 8
421 8 T421fsX, T421M,
525 9 K525N, K525N,
565 9
567 9 I567T, I567M,
528 9 R528W, R528X, R528P,
559 10 L559F, L559H,
432 10
420 10 Y420C,
611 10 Y611D,
523 10
522 11 G522E,
564 11 L564L,
527 11
569 11 Y569H, Y569C, Y569X,
561 11 A561T, A561P, A561V,
570 11
419 12
560 12 I560fsX, I560M,
456 12 D456Y,
531 12 R531W, R531Del, R531Q,
558 13 A558P, A558E, A558V,
418 13
524 13
615 13 L615V, L615F,
452 13
532 13
614 13 A614T, A614V,
530 13
607 14
568 14 W568C, W568C,
610 14
618 14 T618S, T618S
573 15
571 15 I571L, I571V,
417 15
459 15
612 15 V612L, V612L, V612A,
556 15
574 15 M574L, M574V, M574L,
453 15