KCNH2 Variant I464V

Summary of observed carriers, functional annotations, and structural context for KCNH2 I464V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I464V has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 83% of WT with a standard error of 20%. 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 (%)
-0.523 0.338 3 0.582 54

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 I464V.
Neighbour residue Distance (Å) Observed variants
464 0 I464X,
465 5
461 5
467 6
505 6 A505V,
463 6 F463L, F463L, F463L,
468 7 L468R, L468X, L468F,
462 7 M462Ins,
466 7 D466E, D466E,
460 7 D460fsX,
504 9 A504V,
459 9
502 9 M502I, M502I, M502I,
507 9 P507L, P507S,
506 9 I506V,
469 10
501 10 D501Y, D501H, D501N,
531 10 R531W, R531Q, R531Del,
458 11
457 11 L457P,
470 11 N470D,
503 11
498 11
534 11 R534C,
471 11 F471X,
528 12 R528W, R528P, R528X,
410 12 W410X,
417 12
414 12 I414fsX,
456 13 D456Y,
493 13 Y493Ins, Y493C, Y493H, Y493F,
508 14
500 14 I500Del,
527 14
530 14
418 14
413 14 L413P,
421 14 T421M, T421fsX
472 14 R472X, R472C,
499 15
473 15 T473P,
455 15