KCNH2 Variant G522E

Summary of observed carriers, functional annotations, and structural context for KCNH2 G522E. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

G522E is present in 1 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 98% of WT with a standard error of 8%. 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 (%)
-7.602 1.0 -2 0.822 7

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 1 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 G522E.
Neighbour residue Distance (Å) Observed variants
522 0 G522E,
523 4
521 5
525 5 K525N, K525N,
524 5
520 6
429 6 A429P, A429V,
526 8
428 9 S428fsX, S428X, S428L,
432 9
430 9
508 10
425 10
528 10 R528W, R528X, R528P,
527 10
426 11 P426H,
510 11
509 12 D509N,
431 13 F431L, F431L, F431L,
507 13 P507S, P507L,
529 13
427 13 Y427H, Y427S, Y427C,
574 13 M574L, M574V, M574L
506 14 I506V,
456 14 D456Y,
570 14
566 14 C566S, C566R, C566G, C566S, C566F,
424 15
421 15 T421fsX, T421M,
504 15 A504V,
453 15
503 15