KCNH2 Variant T421K Detail

We estimate the penetrance of LQTS for KCNH2 T421K is 79%. We are unaware of any observations of this variant in individuals. T421K is not present in gnomAD. T421K 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T421K around 79% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.71 0.991 -1 0.947 87
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 3 7 -
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.

T421K has 64 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
421 0 T421M, T421fsX,
422 4 A422T,
420 5 Y420C,
418 5
425 6
531 6 R531W, R531Q, R531Del,
528 6 R528W, R528X, R528P,
419 6
423 6
529 7
417 7
424 7
459 8
532 8
426 8 P426H,
456 9 D456Y,
463 9 F463L, F463L, F463L,
527 9
416 9
530 10
460 10 D460fsX,
526 10
559 10 L559F, L559H,
415 10
563 10 W563C, W563G, W563X, W563C,
504 10 A504V,
525 10 K525N, K525N,
414 10 I414fsX,
428 10 S428fsX, S428L, S428X,
534 11 R534C,
562 11 H562R, H562Q, H562Q, H562P,
455 11
533 12
427 12 Y427H, Y427C, Y427S,
535 12 V535M,
462 12 M462Ins,
458 12
429 12 A429V, A429P,
452 12
413 13 L413P,
457 13 L457P,
505 13 A505V,
555 13
501 13 D501N, D501Y, D501H,
453 13
556 13
503 13
461 13
558 14 A558V, A558P, A558E,
566 14 C566F, C566R, C566G, C566S, C566S,
466 14 D466E, D466E,
560 14 I560M, I560fsX,
507 14 P507S, P507L,
524 14
506 14 I506V,
464 14 I464X,
430 14
500 15 I500Del,
454 15
522 15 G522E,
552 15 L552S,
536 15 A536X,
561 15 A561P, A561T, A561V,
523 15