R689H Summary

SCN5A R689H was found in 10 papers (see below) with a total of 30 carriers: 3 had BrS1, 2 had LQT3, and 3 had other disease. R689H is present in 23 out of 248792 alleles in gnomAD (minor allele frequency of 0.009245%). R689H has been functionally characterized in 2 papers. Other variants at the same resdue are R689C .R689G .R689H .R689L .R689P .R689S . 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 Mild_Hotspot region for Long QT syndrome.

R689H Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2249098520120100
2369205320130001SUDS
1599617020050001VT, Mitral Valve Disease
1641494420050010
2054104120100010
2132146520110100
2834178120170100
1645302420060001SIDS
2674645720161000
2012928320101000
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

R689H 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
22490985 2012 HEK NA NA
23692053 2013 HEK 83.3 -0.7 -0.6 200

R689H 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 0.144 -2.11 benign 0.004 2.545 -0.55 -2 0.582

R689H 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
674 14.7
675 14.2
676 13.7
677 13.2
678 12.6
679 12
680 11.4 R680C
681 10.7
682 10.1
683 9.3 C683R
684 8.5
685 7.6
686 6.6
687 5.4
688 3.8
690 3.8
691 5.4 A691S A691T
692 6.6 Q692K
693 7.6 R693C R693H
694 8.5 Y694C
695 9.3
696 10.1
697 10.7
698 11.4
699 12
700 12.6
701 13.2 P701L
702 13.7
703 14.2
704 14.7