KCNH2 Variant I458S

Summary of observed carriers, functional annotations, and structural context for KCNH2 I458S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

20%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I458S has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 26% of WT with a standard error of 11%. 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 (%)
-5.252 0.992 -3 0.905 83

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 I458S.
Neighbour residue Distance (Å) Observed variants
458 0
459 5
457 5 L457P,
455 5
461 6
454 7
460 7 D460fsX,
456 7 D456Y,
462 7 M462Ins,
453 9
417 9
420 10 Y420C,
463 10 F463L, F463L, F463L,
464 11 I464X,
452 11
465 11
451 12 P451L,
413 12 L413P,
421 12 T421fsX, T421M,
528 12 R528W, R528X, R528P,
531 13 R531W, R531Del, R531Q
416 13
414 13 I414fsX,
507 13 P507S, P507L,
424 13
418 13
505 13 A505V,
410 13 W410X,
466 13 D466E, D466E,
450 13
449 14
504 14 A504V,
425 15
419 15