R526H Summary

SCN5A R526H was found in 7 papers (see below) with a total of 20 carriers: 6 had BrS1, 0 had LQT3, and 4 had other disease. R526H is present in 14 out of 242632 alleles in gnomAD (minor allele frequency of 0.00577%). R526H has been functionally characterized in 2 papers. Other variants at the same resdue are R526C .R526G .R526H .R526L .R526P .R526S . 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 Non_Hotspot region for Long QT syndrome.

R526H Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2479534420140200
2457316420140000
1941232820080001DCM
2332162020130100
2755463220170103CM
2012928320100100
2012928320100100
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

R526H 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
24795344 2014 HEK 75 NA
24573164 2014 HEK 87.5 -1.81 NA

R526H 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 0.464 -0.94 benign 0 2.902 2.91 -2 0.476

R526H 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
511 14.7
512 14.2 T512I
513 13.7 R513C
514 13.2 G514C
515 12.6
516 12
517 11.4
518 10.7
519 10.1
520 9.3 M520V
521 8.5 K521E
522 7.6
523 6.6 R523C R523H
524 5.4 S524Y
525 3.8
527 3.8 G527R G527R
528 5.4 S528R S528R S528R
529 6.6
530 7.6 F530V
531 8.5 T531A
532 9.3 F532C F532L F532L F532L
533 10.1 R533C R533H R533S
534 10.7
535 11.4 R535Q
536 12 D536H
537 12.6
538 13.2
539 13.7
540 14.2
541 14.7