KCNH2 Variant D460A

Summary of observed carriers, functional annotations, and structural context for KCNH2 D460A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

17%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

1

Publications with functional data

D460A has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 76% 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 (%)
-7.413 0.999 -2 0.98 69

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.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
15975984 Xeno 22.3 7.6 None None

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
15975984 Xeno None None None

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 D460A.
Neighbour residue Distance (Å) Observed variants
460 0 D460fsX,
459 4
457 5 L457P,
461 5
456 6 D456Y,
463 6 F463L, F463L, F463L,
458 7
528 7 R528W, R528X, R528P,
464 7 I464X,
505 7 A505V,
507 7 P507S, P507L,
462 8 M462Ins,
531 8 R531W, R531Del, R531Q,
504 8 A504V,
455 9
506 9 I506V,
417 10
421 10 T421fsX, T421M,
420 10 Y420C,
465 10
453 10
454 10
525 10 K525N, K525N,
508 11
527 11
466 11 D466E, D466E,
425 11
418 12
503 12
467 12
502 12 M502I, M502I, M502I,
414 12 I414fsX,
452 12
501 13 D501N, D501H, D501Y,
424 13
534 13 R534C
529 13
530 13
526 13
524 14
509 14 D509N,
422 14 A422T,
468 14 L468F, L468X, L468R,
413 14 L413P,
428 14 S428fsX, S428X, S428L,
416 14
410 14 W410X,
419 14
423 15
532 15