KCNH2 Variant L433V

Summary of observed carriers, functional annotations, and structural context for KCNH2 L433V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

12%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L433V 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 (%)
-2.855 0.63 1 0.832 47

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 L433V.
Neighbour residue Distance (Å) Observed variants
433 0
432 4
434 4
431 5 F431L, F431L, F431L,
435 5 E435X, E435G,
430 7
436 7 T436M,
429 8 A429P, A429V,
437 8
428 8 S428fsX, S428L, S428X,
438 8 E438X, E438K,
427 9 Y427C, Y427S, Y427H,
439 9
426 10 P426H,
440 10 P440L,
425 11
441 11 P441L, P441R,
424 11
442 11
423 12
443 12 T443N, T443fsX,
422 13 A422T,
444 13 E444K, E444D, E444D,
421 13 T421M, T421fsX,
445 13
420 14 Y420C,
446 14
419 14
447 14 Y447X,
418 15
448 15 A448S, A448T