KCNH2 Variant L539V

Summary of observed carriers, functional annotations, and structural context for KCNH2 L539V. 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

L539V 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: 129% of WT with a standard error of 17%. 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 (%)
-2.742 0.967 1 0.868 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 L539V.
Neighbour residue Distance (Å) Observed variants
539 0
540 4 D540fsX,
536 5 A536X,
542 5
543 6 S543fsX,
535 6 V535M,
538 7
541 8 R541C, R541H,
537 9 R537W,
552 9 L552S,
549 9 V549M,
544 10 E544A, E544fsX,
3 10
533 10
415 11
411 11
548 11
674 11 H674Y, H674fsX,
670 11
412 11 W412X,
532 11
553 11 L553V,
534 12 R534C,
673 12
667 12 Y667X,
545 12
546 13
497 13 W497X, W497L,
414 13 I414fsX,
556 13
4 13
551 13 F551L, F551L, F551L,
408 13
418 13
671 14 A671G, A671Del,
555 14
547 14 A547T,
550 14
658 14
669 14 G669C, G669R, G669X,
407 14
677 15 M677T,
419 15
402 15 H402R,
662 15
702 15