KCNH2 Variant G522E Detail

We estimate the penetrance of LQTS for KCNH2 G522E is 9%. This variant was found in a total of 1 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. G522E is present in 1 alleles in gnomAD. 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. G522E has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G522E around 9% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.602 1.0 -2 0.822 7
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 -
VARIANT FEATURES ALONE: - 10 9 1 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

G522E has 32 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: 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 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

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