KCNH2 Variant I461T

Summary of observed carriers, functional annotations, and structural context for KCNH2 I461T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I461T has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 27% of WT with a standard error of 14%. 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 (%)
-4.264 0.973 -1 0.946 64

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 I461T.
Neighbour residue Distance (Å) Observed variants
461 0
462 5 M462Ins,
460 5 D460fsX,
464 5 I464X,
458 6
459 6
465 6
457 6 L457P,
463 7 F463L, F463L, F463L,
505 9 A505V,
456 9 D456Y,
466 10 D466E, D466E,
507 10 P507L, P507S,
455 10
417 11
467 11
468 11 L468F, L468R, L468X,
454 11
531 11 R531W, R531Del, R531Q,
504 11 A504V,
528 12 R528P, R528W, R528X,
410 12 W410X,
506 12 I506V,
414 12 I414fsX,
469 12
453 13
413 13 L413P,
420 13 Y420C,
421 13 T421fsX, T421M,
502 14 M502I, M502I, M502I,
418 14
534 14 R534C,
501 14 D501H, D501Y, D501N,
470 15 N470D,
508 15
503 15
416 15