KCNH2 Variant A422P

Summary of observed carriers, functional annotations, and structural context for KCNH2 A422P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

31%

3/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A422P 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 5%. 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 (%)
-4.758 0.999 -1 0.918 86

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 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 A422P.
Neighbour residue Distance (Å) Observed variants
422 0 A422T,
423 4
421 4 T421M, T421fsX,
419 6
425 6
559 6 L559H, L559F,
563 6 W563X, W563G, W563C, W563C,
529 6
426 6 P426H,
418 7
420 7 Y420C,
424 7
562 7 H562P, H562Q, H562R, H562Q,
532 8
531 9 R531Q, R531Del, R531W,
528 9 R528X, R528P, R528W,
417 10
558 10 A558V, A558E, A558P,
555 10
556 10
560 10 I560fsX, I560M,
526 10
427 10 Y427C, Y427S, Y427H,
428 11 S428X, S428fsX, S428L,
566 11 C566S, C566S, C566R, C566G, C566F,
416 11
530 11
415 11
527 11
561 11 A561T, A561P, A561V,
429 12 A429V, A429P,
456 12 D456Y,
459 12
535 12 V535M,
525 12 K525N, K525N,
533 12
564 12 L564L,
565 12
463 13 F463L, F463L, F463L,
414 13 I414fsX,
430 13
552 13 L552S,
534 13 R534C,
611 13 Y611D,
504 13 A504V,
567 13 I567T, I567M,
557 14
460 14 D460fsX,
431 14 F431L, F431L, F431L,
452 14
615 14 L615F, L615V,
551 14 F551L, F551L, F551L,
455 14
536 15 A536X,
413 15 L413P,