E446K Summary

SCN5A E446K was found in 4 papers (see below) with a total of 154 carriers: 0 had BrS1, 0 had LQT3, and 2 had other disease. E446K is present in 154 out of 273176 alleles in gnomAD (minor allele frequency of 0.056374%). E446K has been functionally characterized in 0 papers. Other variants at the same resdue are E446A .E446D .E446D .E446G .E446K .E446Q .E446V . Given the functional data available, we estimate this variant has "Mild_LOF" in vitro character. (LOF and GOF denote loss-of-function and gain-of-function, respectively). This residue is located in a Non_Hotspot region for BrS1 and in a Non_Hotspot region for Long QT syndrome.

E446K Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2233867220120001Post MI TdP
2159623120110001DCM
2510275520140000
2932597620180100
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

E446K Reported Functional Data

Peak current and late current are relative % to 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.

PMID Year Cell type Peak current V0.5 act V0.5 inact Rec from inact Late current
22338672 2012 tsA201 70 -1 -6.16 133.3

E446K 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.

SIFT Sift Score PROVEAN Score Polyphen2 Polyphen2 Score eaRate blastPssm pamScore REVEL
Damaging 0.001 -3.63 probablydamaging 0.959 1.458 0.18 -4 0.732

E446K has 30 neighbors within 15 ångströms that have been found in individuals.

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.

ResidueNumber Distance(Å) Variants
431 14.7
432 14.2
433 13.7 R433C
434 13.2
435 12.6
436 12
437 11.4
438 10.7
439 10.1
440 9.3
441 8.5
442 7.6
443 6.6
444 5.4
445 3.8 H445D
447 3.8 A447G
448 5.4
449 6.6 T449A
450 7.6
451 8.5
452 9.3
453 10.1 V453M
454 10.7
455 11.4
456 12 V456M
457 12.6
458 13.2 R458C R458H
459 13.7
460 14.2
461 14.7 L461V