KCNH2 Variant F508L

Summary of observed carriers, functional annotations, and structural context for KCNH2 F508L. 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

F508L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 98% of WT with a standard error of 21%. 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 (%)
-5.427 0.225 0 0.836 45

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 F508L.
Neighbour residue Distance (Å) Observed variants
508 0
507 5 P507S, P507L,
506 6 I506V,
510 6
509 6 D509N,
524 7
525 8 K525N, K525N,
521 9
505 9 A505V,
522 10 G522E,
528 10 R528W, R528X, R528P,
527 10
503 10
504 10 A504V,
460 11 D460fsX,
523 11
526 11
520 12
502 12 M502I, M502I, M502I,
457 13 L457P,
456 13 D456Y,
531 14 R531W, R531Del, R531Q
464 14 I464X,
425 14
530 15
461 15
429 15 A429P, A429V,
463 15 F463L, F463L, F463L,
459 15