KCNH2 Variant L530C

Summary of observed carriers, functional annotations, and structural context for KCNH2 L530C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

23%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

1

Publications with functional data

L530C has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 119% of WT with a standard error of 12%. 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
None None None None 71

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 8 2 –

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)
19878047 Xeno 21.8 None 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)
19878047 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 L530C.
Neighbour residue Distance (Å) Observed variants
530 0
529 5
527 5
500 6 I500Del,
531 6 R531Q, R531Del, R531W,
533 6
504 6 A504V,
503 7
532 7
501 7 D501H, D501Y, D501N,
534 8 R534C,
528 8 R528W, R528X, R528P,
526 8
502 9 M502I, M502I, M502I,
421 10 T421M, T421fsX,
499 10
505 10 A505V,
418 10
463 10 F463L, F463L, F463L,
422 11 A422T,
497 11 W497X, W497L,
506 11 I506V,
535 11 V535M,
425 11
536 11 A536X,
537 11 R537W,
498 12
525 12 K525N, K525N,
524 12
563 13 W563C, W563X, W563G, W563C,
460 13 D460fsX,
426 13 P426H,
496 13
417 13
466 13 D466E, D466E,
419 13
467 13
414 13 I414fsX,
507 14 P507S, P507L,
538 14
459 14
523 14
420 14 Y420C,
464 14 I464X,
415 14
423 14
508 15
559 15 L559H, L559F,
493 15 Y493H, Y493Ins, Y493C, Y493F,