KCNH2 Variant T425K Detail

We estimate the penetrance of LQTS for KCNH2 T425K is 50%. We are unaware of any observations of this variant in individuals. T425K is not present in gnomAD. T425K has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T425K around 50% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.71 0.63 -1 0.936 56
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 6 4 -
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.

T425K has 60 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
425 0
426 4 P426H,
428 6 S428L, S428fsX, S428X,
421 6 T421M, T421fsX,
528 6 R528W, R528X, R528P,
422 6 A422T,
424 6
423 6
525 7 K525N, K525N,
429 7 A429P, A429V,
526 7
529 7
420 8 Y420C,
427 8 Y427C, Y427H, Y427S,
527 9
456 9 D456Y,
563 9 W563C, W563C, W563X, W563G,
430 9
531 9 R531W, R531Del, R531Q,
562 10 H562R, H562Q, H562Q, H562P,
566 10 C566R, C566G, C566F, C566S, C566S,
522 10 G522E,
523 10
418 10
419 11
431 11 F431L, F431L, F431L,
432 11
524 11
452 11
559 11 L559F, L559H,
530 11
459 11
460 11 D460fsX,
532 12
504 12 A504V,
417 12
453 12
455 13
567 13 I567M, I567T,
565 13
611 13 Y611D,
463 13 F463L, F463L, F463L,
457 13 L457P,
507 14 P507S, P507L,
561 14 A561V, A561T, A561P,
564 14 L564L,
508 14
503 14
505 14 A505V,
569 14 Y569C, Y569X, Y569H,
560 14 I560fsX, I560M,
558 14 A558E, A558P, A558V,
521 14
416 14
506 15 I506V,
570 15
458 15
520 15
454 15
533 15