KCNH2 Variant H492N

Summary of observed carriers, functional annotations, and structural context for KCNH2 H492N. 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

H492N has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 95% of WT with a standard error of 33%. 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 (%)
-6.287 0.226 0 0.763 61

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 H492N.
Neighbour residue Distance (Å) Observed variants
492 0 H492Y,
491 6 V491I,
475 6 Y475C, Y475Del,
493 6 Y493H, Y493C, Y493F, Y493Ins,
489 6 I489F, I489I,
490 7 A490T, A490P,
496 7
494 8 F494Del,
495 8 K495X,
477 8
497 9 W497L, W497X,
476 10 V476I,
483 10 V483I,
488 10 R488C, R488H,
471 10 F471X,
470 10 N470D,
498 10
487 10 G487S, G487R,
474 11 T474I,
473 11 T473P,
537 11 R537W
478 11 A478D,
480 11 E480V,
484 12
486 12
479 13
499 13
482 13 V482A,
501 13 D501N, D501H, D501Y,
481 13
402 13 H402R,
467 14
485 14 H485X,
472 14 R472C, R472X,
500 14 I500Del,
538 14
469 14
4 15
534 15 R534C,