KCNH2 Variant K525W

Summary of observed carriers, functional annotations, and structural context for KCNH2 K525W. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

15%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

1

Publications with functional data

K525W has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 1%. 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 (%)
None None None None 14

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)
16166152 Xeno -29.4 None None 0.5

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)
16166152 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 K525W.
Neighbour residue Distance (Å) Observed variants
525 0 K525N, K525N,
522 5 G522E,
528 5 R528W, R528P, R528X,
524 5
526 6
425 7
523 7
527 7
429 7 A429V, A429P,
428 8 S428L, S428X, S428fsX,
508 8
521 9
426 9 P426H,
507 9 P507L, P507S,
456 9 D456Y,
529 10
520 10
460 10 D460fsX,
421 10 T421M, T421fsX
506 10 I506V,
504 10 A504V,
531 11 R531W, R531Q, R531Del,
432 11
430 11
509 11 D509N,
424 11
503 12
453 12
505 12 A505V,
457 12 L457P,
530 12
510 12
422 12 A422T,
420 12 Y420C,
427 12 Y427C, Y427H, Y427S,
459 12
452 13
423 13
431 13 F431L, F431L, F431L,
463 14 F463L, F463L, F463L,
455 14
566 14 C566S, C566F, C566S, C566G, C566R,
563 15 W563C, W563C, W563X, W563G,
454 15
418 15
502 15 M502I, M502I, M502I,