KCNH2 Variant T425S

Summary of observed carriers, functional annotations, and structural context for KCNH2 T425S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

22%

90% CI: 5.0% – 45.2%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

T425S 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 7%. 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 (%)
-3.807 0.63 1 0.903 56

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 T425S.
Neighbour residue Distance (Å) Observed variants
425 0
426 4 P426H,
428 6 S428fsX, S428X, S428L,
421 6 T421fsX, T421M,
528 6 R528W, R528X, R528P,
422 6 A422T,
424 6
423 6
525 7 K525N, K525N,
429 7 A429P, A429V,
526 7
529 7
420 8 Y420C,
427 8 Y427H, Y427S, Y427C,
527 9
456 9 D456Y,
563 9 W563G, W563C, W563C, W563X,
430 9
531 9 R531W, R531Del, R531Q,
562 10 H562P, H562R, H562Q, H562Q,
566 10 C566S, C566R, C566G, C566S, C566F,
522 10 G522E,
523 10
418 10
419 11
431 11 F431L, F431L, F431L,
432 11
524 11
452 11
559 11 L559F, L559H,
530 11
459 11
460 11 D460fsX,
532 12
504 12 A504V,
417 12
453 12
455 13
567 13 I567T, I567M,
565 13
611 13 Y611D
463 13 F463L, F463L, F463L,
457 13 L457P,
507 14 P507S, P507L,
561 14 A561T, A561P, A561V,
564 14 L564L,
508 14
503 14
505 14 A505V,
569 14 Y569H, Y569C, Y569X,
560 14 I560fsX, I560M,
558 14 A558P, A558E, A558V,
521 14
416 14
506 15 I506V,
570 15
458 15
520 15
454 15
533 15