KCNH2 Variant L416V

Summary of observed carriers, functional annotations, and structural context for KCNH2 L416V. 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

L416V has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 112% of WT with a standard error of 8%. 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 (%)
-2.688 0.407 1 0.827 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 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 L416V.
Neighbour residue Distance (Å) Observed variants
416 0
417 5
415 5
413 5 L413P,
419 6
418 6
414 7 I414fsX,
420 8 Y420C,
412 8 W412X,
421 9 T421fsX, T421M,
551 10 F551L, F551L, F551L,
459 10
411 10
410 10 W410X,
422 11 A422T,
555 11
462 11 M462Ins,
423 11
409 11 V409M, V409L, V409L,
542 11
535 11 V535M,
552 11 L552S,
463 12 F463L, F463L, F463L,
424 12
532 12
531 12 R531W, R531Del, R531Q,
455 12
534 13 R534C,
458 13
559 13 L559F, L559H
548 13
408 13
456 13 D456Y,
556 14
538 14
466 14 D466E, D466E,
460 14 D460fsX,
425 14
558 15 A558P, A558E, A558V,
541 15 R541C, R541H,
407 15
528 15 R528W, R528X, R528P,
529 15
461 15