A490T Summary

KCNH2 A490T was found in 5 papers (see below) with a total of 12 carriers: 7 had LQT2. A490T is not present in gnomAD. A490T has been functionally characterized in 2 papers. Given the functional data available, we estimate this variant has "Severe 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 3 individuals unaffected with LQT2 and 7 individuals affected with LQT2.


A490T Reported Clinical Data

PMID Year Carriers Unaffected LQT2 Other disease
11170080 2001 1 0 1
18808722 2008 7 5 2
20975234 2010 1 0 1
Italy Cohort 2020 3 0 3
Japan Cohort 2020 1 0 1
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

A490T 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)
11170080 2001 HEK293
20975234 2010 CHO 23.9 25.8 100

A490T 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)
11170080 2001 HEK293 61 6.00
20975234 2010 CHO 10 14.10

A490T 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
-1 0.972 -3.697 0.997 0

A490T has 31 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
400 14.7 I400N
466 14.5 D466E
467 11.6
468 12 L468F L468R L468X
469 12.8
470 9.8 N470D
471 6.3 F471X
472 10.1 R472C R472X
473 10.5 T473P
474 11.6 T474I
475 9.5 Y475C Y475Del
476 14.3 V476I
477 13.3
483 11 V483I
484 11
485 10.9 H485X
486 7
487 6 G487R G487S
488 8.6 R488C R488H
489 4.5 I489F I489I
491 3.9 V491I
492 6.7 H492Y
493 6.2 Y493C Y493F Y493H Y493Ins
494 5.2 F494Del
495 10.2 K495X
496 10.5
497 13.2 W497L W497X
498 9.4
499 13.3
501 13.9 D501H D501N D501Y
502 14.3 M502I