KCNH2 Variant L468V

Summary of observed carriers, functional annotations, and structural context for KCNH2 L468V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

10%

90% CI: 0.6% – 28.8%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L468V has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 98% 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-0.989 0.193 2 0.583 52

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 L468V.
Neighbour residue Distance (Å) Observed variants
468 0 L468F, L468X, L468R,
467 5
469 5
465 5
471 6 F471X,
466 7 D466E, D466E,
470 7 N470D,
464 7 I464X,
472 8 R472C, R472X,
473 9 T473P,
493 10 Y493H, Y493C, Y493F, Y493Ins,
462 10 M462Ins,
463 11 F463L, F463L, F463L,
461 11
498 11
505 11 A505V,
400 11 I400N,
410 12 W410X,
501 12 D501N, D501H, D501Y,
502 12 M502I, M502I, M502I,
490 12 A490T, A490P,
398 12 W398L, W398X,
489 12 I489F, I489I,
486 12
407 13
534 13 R534C
494 13 F494Del,
399 13
406 13
504 13 A504V,
474 14 T474I,
460 14 D460fsX,
414 14 I414fsX,
506 15 I506V,
459 15
411 15
531 15 R531W, R531Del, R531Q,