KCNH2 Variant P486A

Summary of observed carriers, functional annotations, and structural context for KCNH2 P486A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

10%

90% CI: 0.6% – 28.5%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

P486A 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: 118% of WT with a standard error of 19%. 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 (%)
-7.013 0.774 -1 0.856 28

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 P486A.
Neighbour residue Distance (Å) Observed variants
486 0
487 4 G487S, G487R,
485 5 H485X,
489 6 I489F, I489I,
472 6 R472C, R472X,
490 7 A490T, A490P,
488 7 R488C, R488H,
484 7
471 8 F471X,
491 10 V491I,
398 10 W398L, W398X,
473 10 T473P,
483 10 V483I,
399 10
474 10 T474I,
475 11 Y475C, Y475Del,
400 11 I400N,
493 12 Y493H, Y493C, Y493F, Y493Ins,
492 12 H492Y,
470 12 N470D,
494 12 F494Del
468 12 L468F, L468X, L468R,
469 13
401 14
482 14 V482A,
467 14