KCNH2 Variant V465E

Summary of observed carriers, functional annotations, and structural context for KCNH2 V465E. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

18%

90% CI: 3.0% – 39.6%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V465E 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 5%. 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 (%)
-5.393 0.969 -3 0.967 56

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 V465E.
Neighbour residue Distance (Å) Observed variants
465 0
464 5 I464X,
466 5 D466E, D466E,
468 5 L468F, L468X, L468R,
462 5 M462Ins,
469 6
467 6
461 6
463 7 F463L, F463L, F463L,
410 8 W410X,
470 9 N470D,
460 10 D460fsX,
459 10
505 10 A505V,
471 10 F471X,
414 10 I414fsX,
458 11
534 11 R534C
407 12
413 12 L413P,
472 12 R472C, R472X,
417 12
501 12 D501N, D501H, D501Y,
406 12
473 12 T473P,
504 12 A504V,
531 12 R531W, R531Del, R531Q,
502 13 M502I, M502I, M502I,
411 13
457 13 L457P,
400 13 I400N,
493 13 Y493H, Y493C, Y493F, Y493Ins,
498 13
507 14 P507S, P507L,
506 14 I506V,
418 14
409 15 V409M, V409L, V409L,
456 15 D456Y,