KCNH2 Variant S428T

Summary of observed carriers, functional annotations, and structural context for KCNH2 S428T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

17%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

S428T 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: 88% of WT with a standard error of 6%. 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-2.363 0.125 1 0.678 38

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 9 1 –

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 S428T.
Neighbour residue Distance (Å) Observed variants
428 0 S428L, S428X, S428fsX,
429 4 A429V, A429P,
427 5 Y427C, Y427H, Y427S,
425 6
432 6
426 6 P426H,
430 6
431 7 F431L, F431L, F431L,
424 7
525 8 K525N, K525N,
522 9 G522E,
452 9
423 9
566 10 C566S, C566F, C566S, C566G, C566R,
456 10 D456Y,
528 10 R528W, R528P, R528X,
526 10
420 10 Y420C,
523 10
421 10 T421M, T421fsX
422 11 A422T,
453 11
562 11 H562Q, H562Q, H562P, H562R,
611 11 Y611D,
569 12 Y569H, Y569C, Y569X,
607 12
520 12
529 12
524 12
563 12 W563C, W563C, W563X, W563G,
450 13
527 13
565 13
570 13
455 13
521 13
567 13 I567T, I567M,
451 14 P451L,
610 14
460 14 D460fsX,
459 14
457 14 L457P,
454 14
573 14
531 14 R531W, R531Q, R531Del,
608 14
559 15 L559F, L559H,
419 15