R433C Summary

SCN5A R433C was found in 1 paper (see below) with a total of 3 carriers: 0 had BrS1, 0 had LQT3, and 1 had other disease. R433C is present in 3 out of 248502 alleles in gnomAD (minor allele frequency of 0.001207%). R433C has been functionally characterized in 1 paper. Other variants at the same resdue are R433C .R433G .R433H .R433L .R433P .R433S . Given the functional data available, we estimate this variant has "Partial_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.

R433C Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2916711320180001IBS
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

R433C 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
29167113 2018 HEK 42.7 -2.2 -16.5 NA

R433C 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 -4.63 probablydamaging 0.978 1.216 -4.43 -8 0.589

R433C 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
418 14.7
419 14.2
420 13.7
421 13.2
422 12.6
423 12
424 11.4 I424M
425 10.7
426 10.1
427 9.3
428 8.5 E428K
429 7.6 E429K p.E429del
430 6.6
431 5.4
432 3.8
434 3.8
435 5.4
436 6.6
437 7.6
438 8.5
439 9.3
440 10.1
441 10.7
442 11.4
443 12
444 12.6
445 13.2 H445D
446 13.7 E446K
447 14.2 A447G
448 14.7