KCNH2 Variant V533L

Summary of observed carriers, functional annotations, and structural context for KCNH2 V533L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

21%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V533L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 47% 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-2.875 0.771 1 0.839 72

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 8 2 –

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 V533L.
Neighbour residue Distance (Å) Observed variants
533 0
532 5
534 5 R534C,
536 6 A536X,
535 6 V535M,
530 6
537 6 R537W,
500 7 I500Del,
497 7 W497X, W497L,
501 7 D501H, D501N, D501Y,
531 8 R531W, R531Q, R531Del,
538 8
529 9
418 9
504 10 A504V,
539 10
527 11
503 11
463 11 F463L, F463L, F463L,
414 11 I414fsX,
499 11
496 11
415 11
502 11 M502I, M502I, M502I,
421 12 T421fsX, T421M,
498 12
422 12 A422T,
542 12
466 12 D466E, D466E,
419 13
411 13
528 13 R528P, R528W, R528X,
417 13
493 13 Y493H, Y493C, Y493F, Y493Ins,
505 13 A505V,
470 13 N470D,
467 13
540 14 D540fsX,
526 14
552 14 L552S,
556 14
563 14 W563X, W563G, W563C, W563C,
559 14 L559F, L559H,
541 15 R541C, R541H,
425 15