KCNH2 Variant V418F

Summary of observed carriers, functional annotations, and structural context for KCNH2 V418F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

15%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V418F has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 37%. 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 (%)
-4.758 0.94 -1 0.961 81

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 V418F.
Neighbour residue Distance (Å) Observed variants
418 0
419 4
417 5
421 5 T421M, T421fsX,
415 5
532 6
414 6 I414fsX,
531 6 R531Q, R531Del, R531W,
416 6
422 7 A422T,
420 7 Y420C,
535 8 V535M,
534 8 R534C,
463 8 F463L, F463L, F463L,
529 9
459 9
413 9 L413P,
423 9
533 9
528 10 R528W, R528X, R528P,
530 10
559 10 L559H, L559F,
425 10
424 11
411 11
462 11 M462Ins,
555 11
542 11
538 11
412 11 W412X,
504 11 A504V,
536 11 A536X,
552 11 L552S,
466 12 D466E, D466E,
460 12 D460fsX,
410 12 W410X,
556 12
456 12 D456Y,
501 12 D501H, D501Y, D501N,
563 12 W563C, W563X, W563G, W563C,
527 12
537 12 R537W,
551 13 F551L, F551L, F551L,
426 13 P426H,
458 13
539 13
562 13 H562Q, H562P, H562Q, H562R,
455 13
558 14 A558E, A558P, A558V
505 14 A505V,
526 14
461 14
500 14 I500Del,
464 14 I464X,
465 14
409 14 V409L, V409L, V409M,
560 15 I560M, I560fsX,
503 15
525 15 K525N, K525N,
467 15
541 15 R541C, R541H,