KCNH2 Variant F498L

Summary of observed carriers, functional annotations, and structural context for KCNH2 F498L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

16%

1/11 effective observations

Total carriers

1

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F498L is present in 1 alleles in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 89% 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 (%)
-5.56 0.783 0 0.93 70

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 – 1 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 F498L.
Neighbour residue Distance (Å) Observed variants
498 0
493 5 Y493H, Y493C, Y493F, Y493Ins,
502 5 M502I, M502I, M502I,
499 5
501 6 D501N, D501H, D501Y,
494 6 F494Del,
496 7
500 7 I500Del,
467 7
497 8 W497L, W497X,
471 9 F471X,
503 9
470 9 N470D,
495 9 K495X,
490 9 A490T, A490P,
505 10 A505V,
504 10 A504V,
534 10 R534C,
492 10 H492Y,
466 10 D466E, D466E,
468 11 L468F, L468X, L468R,
491 11 V491I,
537 11 R537W
506 11 I506V,
464 11 I464X,
530 12
489 12 I489F, I489I,
533 12
463 12 F463L, F463L, F463L,
469 12
531 13 R531W, R531Del, R531Q,
465 13
473 13 T473P,
527 14
538 14
475 14 Y475C, Y475Del,
472 15 R472C, R472X,