KCNH2 Variant R488H

Summary of observed carriers, functional annotations, and structural context for KCNH2 R488H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

5%

0/16 effective observations

Total carriers

6

0 LQT2 · 4 unaffected

Functional studies

0

Publications with functional data

R488H is present in 6 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 65% of WT with a standard error of 29%. 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 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-3.785 0.999 0 0.713 8

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 – 6 4 0 –
Variant features alone – 10 10 0 –

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 R488H.
Neighbour residue Distance (Å) Observed variants
488 0 R488C, R488H,
487 5 G487S, G487R,
484 6
483 6 V483I,
489 6 I489F, I489I,
485 7 H485X,
486 7
491 8 V491I,
490 9 A490T, A490P,
475 9 Y475C, Y475Del,
480 10 E480V,
492 10 H492Y,
482 10 V482A,
477 10
474 11 T474I,
481 12
473 12 T473P,
476 12 V476I,
472 12 R472C, R472X,
471 13 F471X,
479 13
494 13 F494Del,
9 13 A9T, A9V,
493 13 Y493H, Y493C, Y493F, Y493Ins,
478 14 A478D,
399 14
17 14
8 15
13 15 T13N
400 15 I400N,
398 15 W398L, W398X,
470 15 N470D,