E462K Summary

SCN5A E462K was found in 2 papers (see below) with a total of 8 carriers: 0 had BrS1, 1 had LQT3, and 0 had other disease. E462K is present in 7 out of 248440 alleles in gnomAD (minor allele frequency of 0.002818%). E462K has been functionally characterized in 1 paper. Other variants at the same resdue are E462A .E462D .E462D .E462G .E462K .E462Q .E462V . Given the functional data available, we estimate this variant has "Normal" 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 Mild_Hotspot region for Long QT syndrome.

E462K Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2590454120150000
1584047620050010
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

E462K 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
25904541 2015 HEK 91 -2 -3 85

E462K 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
Tolerated 0.237 -2.9 probablydamaging 0.972 2.502 -0.13 -4 0.787

E462K 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
447 14.7 A447G
448 14.2
449 13.7 T449A
450 13.2
451 12.6
452 12
453 11.4 V453M
454 10.7
455 10.1
456 9.3 V456M
457 8.5
458 7.6 R458C R458H
459 6.6
460 5.4
461 3.8 L461V
463 3.8 M463R
464 5.4
465 6.6
466 7.6 L466F L466F
467 8.5
468 9.3 P468L
469 10.1
470 10.7 N470K N470K
471 11.4
472 12
473 12.6
474 13.2 R474K
475 13.7 R475K R475S R475S
476 14.2
477 14.7