KCNH2 Variant I469M

Summary of observed carriers, functional annotations, and structural context for KCNH2 I469M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

25%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I469M has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 20% of WT with a standard error of 20%. 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 (%)
-2.78 0.985 1 0.839 67

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 I469M.
Neighbour residue Distance (Å) Observed variants
469 0
470 5 N470D,
468 5 L468F, L468X, L468R,
466 5 D466E, D466E,
473 6 T473P,
465 6
467 7
471 7 F471X,
472 7 R472C, R472X,
400 8 I400N,
407 8
410 8 W410X,
406 9
464 10 I464X,
462 10 M462Ins,
474 10 T474I,
493 10 Y493H, Y493C, Y493F, Y493Ins,
411 11
463 11 F463L, F463L, F463L,
399 11
401 11
414 11 I414fsX,
398 11 W398L, W398X,
534 11 R534C,
489 11 I489F, I489I,
402 12 H402R,
404 12
501 12 D501N, D501H, D501Y,
408 12
498 12
538 12
461 12
486 13
490 13 A490T, A490P,
413 13 L413P,
537 13 R537W,
409 13 V409M, V409L, V409L,
475 13 Y475C, Y475Del,
405 14
505 14 A505V,
484 14
502 14 M502I, M502I, M502I,
485 14 H485X,
492 14 H492Y,
541 15 R541C, R541H
417 15
494 15 F494Del,
403 15
504 15 A504V,
531 15 R531W, R531Del, R531Q,
459 15
483 15 V483I,