KCNH2 Variant T526S Detail

We estimate the penetrance of LQTS for KCNH2 T526S is 26%. We are unaware of any observations of this variant in individuals. T526S is not present in gnomAD. T526S 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T526S around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.826 0.756 1 0.868 37
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 8 2 -
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.

T526S has 47 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
526 0
527 4
529 6
525 6 K525N, K525N,
523 6
524 6
528 6 R528W, R528X, R528P,
425 7
522 8 G522E,
426 8 P426H,
429 8 A429P, A429V,
530 8
421 10 T421M, T421fsX,
531 10 R531W, R531Del, R531Q,
428 10 S428L, S428fsX, S428X,
504 10 A504V,
503 10
422 10 A422T,
430 11
563 11 W563C, W563C, W563X, W563G,
521 11
508 11
506 12 I506V,
532 12
566 12 C566R, C566G, C566F, C566S, C566S,
423 12
507 13 P507S, P507L,
424 13
505 13 A505V,
567 13 I567M, I567T,
500 13 I500Del,
520 13
456 13 D456Y,
427 13 Y427C, Y427H, Y427S,
460 13 D460fsX,
420 13 Y420C,
432 13
418 14
533 14
502 14 M502I, M502I, M502I,
562 14 H562R, H562Q, H562Q, H562P,
431 14 F431L, F431L, F431L,
501 14 D501H, D501Y, D501N,
463 14 F463L, F463L, F463L,
570 14
559 15 L559F, L559H,
459 15