RYR2 G1885E - GET-Evidence

Curation:
Currentness:

RYR2 G1885E

(RYR2 Gly1885Glu)


Short summary

Hypothesized to cause arrhythmogenic right ventricular cardiomyopathy when compound heterozygous with G1886S. However, this variant is quite common (2.4% in Europeans), as is G1886S (3.1% in Europeans), and about 1 in 700 are compound heterozygous. This is highly discordant with a disease prevalence of 1 in 2500 to 5000, and notably G1886S is reported in ClinVar as benign. We should consider the original hypothesis disproven.

Variant evidence
Computational
Functional

Has a functional impact leading to some enhanced responsiveness

See Koop A et al. 2008 (18326664).

Case/Control 5

p=0.029 for pathogenic effect when compound heterozygous with G1886S, after correcting for multiple hypotheses.

See Milting H et al. 2006 (16769042).

Familial

No familial data

See Milting H et al. 2006 (16769042).

 
Clinical importance
Severity -

ARVC

Treatability - implantable cardioverter defibrillator, medication
Penetrance

Presumed moderate-high penetrance based on the numbers reported by Milting et al., as none of the controls had this genotype.

See Milting H et al. 2006 (16769042).

 

Impact

Low clinical importance, Likely benign

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr1:237778082: 1.8% (180/10046) in EVS
  • A @ chr1:235844704: 2.4% (3/126) in GET-Evidence
  • Frequency shown in summary reports: 1.8% (180/10046)

Publications
 

Milting H, Lukas N, Klauke B, Körfer R, Perrot A, Osterziel KJ, Vogt J, Peters S, Thieleczek R, Varsányi M. Composite polymorphisms in the ryanodine receptor 2 gene associated with arrhythmogenic right ventricular cardiomyopathy. Cardiovasc Res. 2006 Aug 1;71(3):496-505. Epub 2006 Apr 18. PubMed PMID: 16769042.

These authors report that the compound heterozygous state of G1885E/G1886S is pathogenic and associated with ARVC, but that neither alone heterozygously no G1885E homozygously is associated with it. They screened 85 ARVC cases, 79 dilated cardiomyopathy, and 463 controls from blood donors.

In ARVC cases, they found: + / +: 75, +/G1886S: 5, +/G1885E: 2, G1885E/G1885E: 0, G1885E/G1886S: 3
In DCM cases they found: + / +: 68, +/G1886S: 5, +/G1885E: 6, G1885E/G1885E: 0, G1885E/G1886S: 0
In controls they found: + / +: 397, +/G1886S: 36, +/G1885E: 28, G1885E/G1885E: 2, G1885E/G1886S: 0

Using a two-tailed Fisher’s Exact test, the 3/85 ARVC compound heterozygotes compared to the incidence in controls (0/397) has a significance of p=0.00362, which the authors report as significant. However, there are many hypotheses being examined here — four different genotypes and two diseases — we could estimate 8 hypotheses have been examined for significance. Applying a Bonferroni correction by multiplying this by 8, this is a corrected p-value of 0.029.

Koop A, Goldmann P, Chen SR, Thieleczek R, Varsányi M. ARVC-related mutations in divergent region 3 alter functional properties of the cardiac ryanodine receptor. Biophys J. 2008 Jun;94(12):4668-77. Epub 2008 Mar 7. PubMed PMID: 18326664; PubMed Central PMCID: PMC2397357.

This variant (G1885E) and G1886S are investigated for their effect on protein function. Either variant alone led to enhanced channel activity, with a significant increase in the store-overload-induced calcium release activity of the corresponding cells. When both were present within the same protein, there was a severe loss of function. As the authors note, however, this cis configuration is unlikely to be the genotype present in the cases reported by Milting et al. (much more likely to have been compound heterozygous with the variants on two different genes).

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het A @ chr1:237778082

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr1:237778082

 

GS12004 - var-GS12004-1100-36-ASM
het A @ chr1:235844705

 

Other external references
 

    dbSNP
  • rs41315858
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the RYR2 gene
    Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 2
    Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autos
    Catecholaminergic Polymorphic Ventricular Tachycardia
    RYR2-Related Catecholaminergic Polymorphic Ventricular Tachycard
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RYR2
    Web search results (48 hits -- see all)
  • ARVC-Related Mutations in Divergent Region 3 Alter Functional ...
    Two possible compositions resulting from homozygous combinations are given by RyR2-G1885E and RyR2-G1886S, respectively, which were recombinantly generated. ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2397357/?tool=pubmed
  • Sunday, March 1, 2009
    A common RyR2 polymorphism (G1885E) modulates the caffeine-sensitivity ... A G1885E RyR2 Polymorphism Modulates The Caffeine Sensitivity Of An ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • Biophysical Journal - ARVC-Related Mutations in Divergent ...
    A G1885E RyR2 Polymorphism Modulates The Caffeine Sensitivity Of An Arrhythmia-linked ... receptor (RyR2) leading to the nonsynonymous amino acid replacements G1885E and G1886S ...
    www.cell.com/biophysj/abstract/S0006-3495(08)70334-5
  • Composite polymorphisms in the ryanodine receptor 2 gene ...
    RyR2 G1885E/G1886 was found in 2 out of 463 blood donors (genotype T3) but not in ARVC and DCM patients. ... expressing RyR2 G1885E/G1886 and G1885/G1886S but not a RyR2 monomer ...
    cardiovascres.oxfordjournals.org/cgi/content/full/71/3/496
  • Biophysical Journal - Assessment of Sarcoplasmic Reticulum ...
    ... (RyR2) leading to the nonsynonymous amino acid replacements G1885E and ... RyR2 mutants associated with arrhythmogenic right ventricular cardiomyopathy, RyR2-G1885E, RyR2-G1886S, ...
    www.cell.com/biophysj/abstract/S0006-3495(09)00424-X
  • Ryanodine Receptors Type II
    ther insight into the role of RyR2-bound CaM in the process of development ... A common RyR2 polymorphism (G1885E) modulates the caffeine-sensitivity ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • Biophysical Journal RSS Page 21
    Biophysical Journal RSS Page 21 ... lines isogenically expressing RyR2 mutants associated with ARVC, RyR2-G1885E, RyR2-G1886S, RyR2-G1886D (mimicking a ...
    medworm.com/rss/search.php?qu=Biophysical+Journal&...
  • CONTICA - Control of Intracellular Calcium and Arrhythmias ...
    Title: G1885E RyR2 Polymorphism Modulates The Caffeine Sensitivity Of An Arrhythmia-linked Mutation. ... Title: Serum factors promote RyR2 molecular instability and Ca2+ ...
    www.contica.eu/178.htm
  • WikiGenes - RYR2 - ryanodine receptor 2 (cardiac)
    The world's first wiki where authorship really matters. Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts.
    www.wikigenes.org/e/gene/e/6262.html
  • Identification of mutations in the cardiac ryanodine receptor ...
    substitutions in the RyR2 sequence (G1885E and Q2958R) were carried in cis with the ... (C) Family 122: DNA sequencing of RYR2 exon 15 in all family members ...
    hmg.oxfordjournals.org/cgi/reprint/10/3/189.pdf

Other in silico analyses
 

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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