KCNH2 Variant G496D

Summary of observed carriers, functional annotations, and structural context for KCNH2 G496D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

21%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

G496D has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 44% of WT with a standard error of 17%. 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 (%)
-6.487 1.0 -2 0.958 81

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 G496D.
Neighbour residue Distance (Å) Observed variants
496 0
497 5 W497L, W497X,
495 5 K495X,
499 6
493 7 Y493H, Y493C, Y493F, Y493Ins,
498 7
492 7 H492Y,
494 7 F494Del,
500 8 I500Del,
501 9 D501N, D501H, D501Y,
537 9 R537W
491 10 V491I,
490 11 A490T, A490P,
502 11 M502I, M502I, M502I,
533 11
470 12 N470D,
534 12 R534C,
489 12 I489F, I489I,
471 12 F471X,
475 12 Y475C, Y475Del,
467 13
503 13
530 13
536 13 A536X,
538 13
504 14 A504V,
477 14
466 14 D466E, D466E,
476 15 V476I,
473 15 T473P,