KCNH2 Variant A429P

Summary of observed carriers, functional annotations, and structural context for KCNH2 A429P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

31%

4/13 effective observations

Total carriers

3

2 LQT2 · 1 unaffected

Functional studies

1

Publications with functional data

A429P 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: 0% of WT with a standard error of 0%. 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 (%)
-4.758 0.121 -1 0.934 39

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
19668779 2009 3 1 2
Literature, cohort, and gnomAD – 3 1 2 –
Variant features alone – 10 8 2 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
19668779 Xeno None None None None

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
19668779 Xeno 40 -2.9 7.0 None

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 A429P.
Neighbour residue Distance (Å) Observed variants
429 0 A429P, A429V,
430 4
428 4 S428fsX, S428X, S428L,
426 5 P426H,
432 6
522 6 G522E,
431 7 F431L, F431L, F431L,
425 7
523 7
427 7 Y427H, Y427S, Y427C,
525 7 K525N, K525N,
526 8
566 8 C566S, C566R, C566G, C566S, C566F,
569 10 Y569H, Y569C, Y569X,
570 10
424 10
520 10
524 10
528 11 R528W, R528X, R528P,
567 11 I567T, I567M,
521 11
423 11
562 12 H562P, H562R, H562Q, H562Q,
529 12
422 12 A422T,
563 12 W563G, W563C, W563C, W563X,
574 12 M574L, M574V, M574L,
573 12
527 12
565 12
421 12 T421fsX, T421M,
611 12 Y611D,
607 13
456 13 D456Y,
452 13
420 13 Y420C,
610 14
571 14 I571L, I571V,
572 14 G572S, G572R, G572C, G572D,
564 14 L564L,
453 14
508 15
614 15 A614T, A614V