KCNH2 Variant A490D

Summary of observed carriers, functional annotations, and structural context for KCNH2 A490D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

22%

90% CI: 4.9% – 45.0%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A490D has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 10%. 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 (%)
-5.553 0.999 -2 0.984 71

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 A490D.
Neighbour residue Distance (Å) Observed variants
490 0 A490T, A490P,
491 4 V491I,
489 4 I489F, I489I,
494 5 F494Del,
487 6 G487S, G487R,
493 6 Y493H, Y493C, Y493F, Y493Ins,
471 6 F471X,
492 7 H492Y,
486 7
488 9 R488C, R488H,
498 9
475 10 Y475C, Y475Del,
470 10 N470D,
472 10 R472C, R472X,
495 10 K495X,
473 10 T473P,
496 11
485 11 H485X,
483 11 V483I,
484 11
467 12
474 12 T474I,
468 12 L468F, L468X, L468R,
469 13
497 13 W497L, W497X,
477 13
499 13
501 14 D501N, D501H, D501Y,
476 14 V476I,
502 14 M502I, M502I, M502I
466 15 D466E, D466E,
400 15 I400N,