KCNH2 Variant K525E Detail

We estimate the penetrance of LQTS for KCNH2 K525E is 15%. We are unaware of any observations of this variant in individuals. K525E is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% 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. K525E has not been functionally characterized. This residue is located in a Mild_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 K525E around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.834 0.988 1 0.949 14
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: - 0 0 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.

K525E has 46 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
525 0 K525N, K525N,
522 5 G522E,
528 5 R528W, R528P, R528X,
524 5
526 6
425 7
523 7
527 7
429 7 A429P, A429V,
428 8 S428fsX, S428X, S428L,
508 8
521 9
426 9 P426H,
507 9 P507S, P507L,
456 9 D456Y,
529 10
520 10
460 10 D460fsX,
421 10 T421fsX, T421M,
506 10 I506V,
504 10 A504V,
531 11 R531Del, R531Q, R531W,
432 11
430 11
509 11 D509N,
424 11
503 12
453 12
505 12 A505V,
457 12 L457P,
530 12
510 12
422 12 A422T,
420 12 Y420C,
427 12 Y427H, Y427S, Y427C,
459 12
452 13
423 13
431 13 F431L, F431L, F431L,
463 14 F463L, F463L, F463L,
455 14
566 14 C566G, C566S, C566F, C566R, C566S,
563 15 W563C, W563X, W563C, W563G,
454 15
418 15
502 15 M502I, M502I, M502I,