KCNH2 Variant V491A

Summary of observed carriers, functional annotations, and structural context for KCNH2 V491A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

90% CI: 1.3% – 32.9%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V491A has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 94% of WT with a standard error of 31%. 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 (%)
-3.34 0.236 -1 0.679 37

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 V491A.
Neighbour residue Distance (Å) Observed variants
491 0 V491I,
490 4 A490T, A490P,
492 6 H492Y,
494 6 F494Del,
489 6 I489F, I489I,
487 7 G487S, G487R,
488 8 R488C, R488H,
493 8 Y493H, Y493C, Y493F, Y493Ins,
495 8 K495X,
486 10
475 10 Y475C, Y475Del,
496 10
471 10 F471X,
498 11
483 11 V483I,
477 12
484 12
485 13 H485X,
470 13 N470D,
473 13 T473P,
497 13 W497L, W497X
474 13 T474I,
472 14 R472C, R472X,
499 14
480 14 E480V,
476 14 V476I,
467 15
478 15 A478D,