KCNH2 Variant L524P

Summary of observed carriers, functional annotations, and structural context for KCNH2 L524P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

12%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L524P 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: 41% of WT with a standard error of 10%. 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 (%)
-6.709 1.0 -3 0.961 16

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 L524P.
Neighbour residue Distance (Å) Observed variants
524 0
523 5
522 5 G522E,
525 5 K525N, K525N,
521 6
526 6
508 7
527 7
528 9 R528W, R528X, R528P,
506 9 I506V,
520 10
507 10 P507S, P507L,
510 10
503 10
429 10 A429P, A429V,
425 11
504 11 A504V,
509 11 D509N,
529 11
530 12
505 12 A505V,
428 12 S428fsX, S428X, S428L,
426 13 P426H,
531 13 R531W, R531Del, R531Q
430 13
460 14 D460fsX,
502 14 M502I, M502I, M502I,
432 14
456 14 D456Y,
421 14 T421fsX, T421M,