KCNH2 Variant L432R

Summary of observed carriers, functional annotations, and structural context for KCNH2 L432R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

18%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L432R has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 125% of WT with a standard error of 12%. 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 (%)
-5.643 0.963 -2 0.925 56

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 L432R.
Neighbour residue Distance (Å) Observed variants
432 0
428 6 S428fsX, S428X, S428L,
429 6 A429P, A429V,
431 6 F431L, F431L, F431L,
430 6
427 8 Y427H, Y427S, Y427C,
522 9 G522E,
607 9
520 10
426 10 P426H,
569 10 Y569H, Y569C, Y569X,
525 11 K525N, K525N,
425 11
573 11
523 11
566 11 C566S, C566R, C566G, C566S, C566F,
610 12
424 12
452 12
570 12
521 13
611 13 Y611D
574 13 M574L, M574V, M574L,
453 13
450 13
606 13 S606Del, S606P, S606F,
526 13
423 14
608 14
524 14
456 14 D456Y,
565 14
572 14 G572S, G572R, G572C, G572D,
567 14 I567T, I567M,
605 14 P605L,
562 15 H562P, H562R, H562Q, H562Q,
528 15 R528W, R528X, R528P,
609 15 D609N, D609G,