R680H Summary

SCN5A R680H was found in 4 papers (see below) with a total of 1 carrier: 0 had BrS1, 0 had LQT3, and 2 had other disease. R680H is present in 1 out of 31402 alleles in gnomAD (minor allele frequency of 0.003185%). R680H has been functionally characterized in 0 papers. Other variants at the same resdue are R680C .R680G .R680H .R680L .R680P .R680S . 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 Mild_Hotspot region for BrS1 and in a Non_Hotspot region for Long QT syndrome.

R680H Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2138594720110001SCD
1721084120070001SIDS
2267707320120001SUDS
1764659120070000
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

R680H 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
21385947 2011 HEK 103.6 -1.2 -0.9 211.8
17210841 2007 tsA204 110 -1.9 0.1 81.8

R680H 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 0.267 -1.95 benign 0 2.201 1.2 -2 0.572

R680H 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
665 14.7 A665S A665T
666 14.2
667 13.7
668 13.2 V668I
669 12.6
670 12
671 11.4
672 10.7 A672T
673 10.1
674 9.3
675 8.5
676 7.6
677 6.6
678 5.4
679 3.8
681 3.8
682 5.4
683 6.6 C683R
684 7.6
685 8.5
686 9.3
687 10.1
688 10.7
689 11.4 R689C R689H
690 12
691 12.6 A691S A691T
692 13.2 Q692K
693 13.7 R693C R693H
694 14.2 Y694C
695 14.7