KCNH2 Variant T421P

Summary of observed carriers, functional annotations, and structural context for KCNH2 T421P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

24%

90% CI: 6.3% – 48.3%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

T421P 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 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 (%)
-5.71 0.937 -1 0.955 87

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 T421P.
Neighbour residue Distance (Å) Observed variants
421 0 T421fsX, T421M,
422 4 A422T,
420 5 Y420C,
418 5
425 6
531 6 R531W, R531Del, R531Q,
528 6 R528W, R528X, R528P,
419 6
423 6
529 7
417 7
424 7
459 8
532 8
426 8 P426H,
456 9 D456Y,
463 9 F463L, F463L, F463L,
527 9
416 9
530 10
460 10 D460fsX,
526 10
559 10 L559F, L559H,
415 10
563 10 W563G, W563C, W563C, W563X,
504 10 A504V,
525 10 K525N, K525N,
414 10 I414fsX,
428 10 S428fsX, S428X, S428L,
534 11 R534C,
562 11 H562P, H562R, H562Q, H562Q,
455 11
533 12
427 12 Y427H, Y427S, Y427C,
535 12 V535M,
462 12 M462Ins,
458 12
429 12 A429P, A429V,
452 12
413 13 L413P,
457 13 L457P,
505 13 A505V,
555 13
501 13 D501N, D501H, D501Y,
453 13
556 13
503 13
461 13
558 14 A558P, A558E, A558V,
566 14 C566S, C566R, C566G, C566S, C566F
466 14 D466E, D466E,
560 14 I560fsX, I560M,
507 14 P507S, P507L,
524 14
506 14 I506V,
464 14 I464X,
430 14
500 15 I500Del,
454 15
522 15 G522E,
552 15 L552S,
536 15 A536X,
561 15 A561T, A561P, A561V,
523 15