KCNH2 Variant V459G

Summary of observed carriers, functional annotations, and structural context for KCNH2 V459G. 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

V459G has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 90% 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 (%)
-6.487 0.993 -3 0.947 77

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 V459G.
Neighbour residue Distance (Å) Observed variants
459 0
460 4 D460fsX,
458 5
456 5 D456Y,
462 6 M462Ins,
417 6
463 6 F463L, F463L, F463L,
461 6
457 6 L457P,
420 7 Y420C,
455 7
421 8 T421fsX, T421M,
531 8 R531Del, R531Q, R531W,
528 8 R528X, R528W, R528P,
418 9
464 9 I464X,
454 10
414 10 I414fsX,
465 10
453 10
413 10 L413P,
416 10
504 10 A504V,
505 10 A505V,
424 11
466 11 D466E, D466E,
419 11
425 11
452 11
507 11 P507L, P507S,
410 12 W410X,
422 12 A422T,
534 12 R534C,
415 12
525 12 K525N, K525N,
423 13
527 13
529 13
506 13 I506V,
467 13
532 14
501 14 D501H, D501Y, D501N,
451 14 P451L,
530 14
428 14 S428L, S428fsX, S428X,
503 14
502 15 M502I, M502I, M502I,
411 15
426 15 P426H,
468 15 L468F, L468R, L468X,
526 15
508 15
469 15