D456Y Summary

KCNH2 D456Y was found in 2 papers (see below) with a total of 1 carrier: 1 had LQT2. D456Y is not present in gnomAD. D456Y has been functionally characterized in 1 paper. Given the functional data available, we estimate this variant has "Dominant LOF" in vitro character. (LOF and GOF denote loss-of-function and gain-of-function, respectively). 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 1 individuals unaffected with LQT2 and 9 individuals affected with LQT2.


D456Y Reported Clinical Data

PMID Year Carriers Unaffected LQT2 Other disease
15840476 2005 1 0 1
19038855 2009 1 0 1 Seizure
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

D456Y Reported Functional Data: heterozygously collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PMID Year Cell type S.S. peak current (%WT) Peak tail current (%WT) V0.5 act V0.5 inact Rec. inact. (%WT) Deactivation (%WT)
16432067 2006 HEK293 45

D456Y Reported Functional Data: homozygously collected

PMID Year Cell type S.S. peak current (%WT) Peak tail current (%WT) V0.5 act V0.5 inact Rec. inact. (%WT) Deactivation (%WT)
16432067 2006 HEK293 20

D456Y Predictions

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 is 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. PAM scores reflect the chemistry difference between WT and variant amino acid (more negative being greater difference between the two). BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected.

PAM Score REVEL Score PROVEAN Score Polyphen2 Score BLAST-PSSM
-11 0.982 -7.948 0.97 -3

D456Y has 47 neighbors (found in individuals) within 15 ångströms

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. This results from the fact that the functional Kv11.1 channel 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.

ResidueNumber Distance(Å) Variants
413 14.9 L413P
414 14.5 I414fsX
416 13.4
417 9.9
418 11.9
419 12.9
420 6.6 Y420C
421 8.5 T421fsX T421M
422 11.8 A422T
423 11.5
424 8.2
425 8.9
426 12.2 P426H
427 12.5 Y427C Y427H Y427S
428 9.8 S428fsX S428L S428X
429 12.9 A429P A429V
432 14.1
449 13.1
450 10.6
451 10 P451L
452 6.7
453 5.3
454 6.6
455 5.1
457 5 L457P
458 6.6
459 5.5
460 5.9 D460fsX
461 9.5
462 10.9 M462Ins
463 10.6 F463L
464 12.8 I464X
465 14.9
504 12.3 A504V
505 12.5 A505V
506 13.6 I506V
507 10.9 P507L P507S
508 13.1
509 14.4 D509N
522 13.7 G522E
524 14.2
525 9.2 K525N
526 13.2
527 12.8
528 7.7 R528P R528W R528X
529 13.3
531 10.5 R531Del R531Q R531W