KCNH2 Variant L499R

Summary of observed carriers, functional annotations, and structural context for KCNH2 L499R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

25%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L499R has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 5%. 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 (%)
-5.285 0.922 -2 0.96 60

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.

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 L499R.
Neighbour residue Distance (Å) Observed variants
499 0
500 4 I500Del,
498 5
502 6 M502I, M502I, M502I,
496 6
501 7 D501N, D501Y, D501H,
503 7
497 8 W497L, W497X,
495 8 K495X,
494 9 F494Del,
493 9 Y493H, Y493F, Y493C, Y493Ins,
530 10
504 10 A504V,
505 11 A505V,
533 11
506 11 I506V,
467 12
534 12 R534C,
537 12 R537W,
527 12
492 13 H492Y,
531 13 R531W, R531Q, R531Del,
490 13 A490T, A490P,
470 13 N470D,
471 14 F471X,
491 14 V491I,
466 14 D466E, D466E
463 14 F463L, F463L, F463L,
464 15 I464X,
529 15
532 15