KCNH2 Variant I419M

Summary of observed carriers, functional annotations, and structural context for KCNH2 I419M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

20%

90% CI: 4.2% – 43.1%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I419M has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 16% 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-2.68 0.598 1 0.78 78

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 I419M.
Neighbour residue Distance (Å) Observed variants
419 0
418 4
416 6
422 6 A422T,
415 6
421 6 T421fsX, T421M,
423 6
417 7
420 7 Y420C,
555 7
559 7 L559F, L559H,
532 8
424 9
414 9 I414fsX,
556 9
552 10 L552S,
551 10 F551L, F551L, F551L,
558 10 A558P, A558E, A558V,
535 10 V535M,
531 10 R531W, R531Del, R531Q,
413 10 L413P,
425 11
562 11 H562P, H562R, H562Q, H562Q,
529 11
563 11 W563G, W563C, W563C, W563X
459 11
412 12 W412X,
426 12 P426H,
542 12
463 12 F463L, F463L, F463L,
534 12 R534C,
560 12 I560fsX, I560M,
528 12 R528W, R528X, R528P,
533 13
554 13
456 13 D456Y,
411 13
553 13 L553V,
561 13 A561T, A561P, A561V,
530 13
557 14
455 14
536 14 A536X,
462 14 M462Ins,
427 14 Y427H, Y427S, Y427C,
548 14
538 14
410 14 W410X,
460 14 D460fsX,
428 15 S428fsX, S428X, S428L,
539 15
458 15
527 15
549 15 V549M,