GABRD R220H - GET-Evidence

Curation:
Currentness:

GABRD R220H

(GABRD Arg220His)


Short summary

Probably benign, one report hypothesized this variant was associated with epilepsy, but a follow-up investigation failed to establish any statistically significant difference for this variant’s incidence in control vs. affected populations.

Variant evidence
Computational 2

Polyphen 2 predicts benign effect, BLOSUM100 score indicates Arg to His is not very disruptive.

Functional -1

Decreased receptor current amplitudes

See Dibbens LM et al. 2004 (15115768).

Case/Control 4

No statistically significant difference in variant incidence

See Lenzen KP et al. 2005 (16023832).

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

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

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr1:1959699: 1.6% (174/10748) in EVS
  • A @ chr1:1949558: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 1.6% (174/10748)

Publications
 

Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, Jenkins M, Petrou S, Sutherland GR, Scheffer IE, Berkovic SF, Macdonald RL, Mulley JC. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet. 2004 Jul 1;13(13):1315-9. Epub 2004 Apr 28. PubMed PMID: 15115768.

The authors report this variant has decreased GABA-A receptor current amplitudes and link it to causing susceptibility to epilepsy.

They screened a combined total of 203 patients (72 with idiopathic epilepsy, 65 with generalized epilepsy with febrile seizures, and 66 with febrile seizures) and report finding the mutation in a single family (heterozygously in the proband) with juvenile myoclonic epilepsy. The variant is homozygous in an affected parent and heterozygous in two affected children, but neither grandparent (parents of the affected parent, necessarily both heterozygous or homozygous carriers themselves) are affected. The authors do not report a LOD score, and penetrance is presumably incomplete according to their pathogenic hypothesis. The variant was not seen in 96 unaffected controls.

Neither familiar data nor case control numbers have statistical significance for this report.

Lenzen KP, Heils A, Lorenz S, Hempelmann A, Sander T. Association analysis of the Arg220His variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy. Epilepsy Res. 2005 Jun;65(1-2):53-7. PubMed PMID: 16023832.

These authors follow up with an association study looking for the relationship between this variant and epilepsy. The authors report that the variant frequency did not differ significantly between the controls and any of the sets of cases they examined (idiopathic generalized epilepsy, myoclonic epilepsy, and idiopathic absence epilepsy).

Genomes
 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het A @ chr1:1959699

 

 

 

Other external references
 

    dbSNP
  • rs41307846
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the GABRD gene
    Juvenile Myoclonic Epilepsy
    GABRD-Related Generalized Epilepsy with Febrile Seizures Plus
    GABRD-Related Juvenile Myoclonic Epilepsy
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GABRD
    PolyPhen-2
  • Score: 0.003 (benign)
    Web search results (47 hits -- see all)
  • URRENT
    GABRD(E177A) and GABRD(R220H). Current Review in Basic Science. 19 ... subunit susceptibility variants E177A and R220H. associated with complex epilepsy alter ...
    aesnet.org/download.cfm?...&showdraft=0&flushcache=0
  • GABRD encoding a protein for extra- or peri-synaptic GABAA ...
    GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility ... containing wild-type, heterozygous R220H or homozygous R220H subunit. ...
    hmg.oxfordjournals.org/cgi/content/full/13/13/1315
  • Juvenile myoclonic epilepsy - Wikipedia, the free encyclopedia
    GABRD encodes the δ subunit of the GABA receptor, which is a subunit ... in this gene associated with JME, E177A, R220C, and R220H, all located in the N-terminus of the protein. ...
    en.wikipedia.org/wiki/Juvenile_myoclonic_epilepsy
  • {delta} Subunit Susceptibility Variants E177A and R220H ...
    Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter ... Implication of GABRD in complex epilepsies. Significant advances have led to some ...
    www.jneurosci.org/cgi/content/full/26/5/1499
  • Juvenile myoclonic epilepsy: Encyclopedia of chemistry ...
    GABRD. GABRD encodes the δ subunit of the GABA receptor, which is a subunit yielding ... R220C mutation but is similar to the R220H mutation, though to a lesser extent than the ...
    www.chemie.de/lexikon/e/Juvenile_myoclonic_epilepsy
  • Susceptibility genes for complex epilepsy -- Mulley et al. 14 ...
    ... of ion channels containing the E177A and R220H variants (40,41) ... GABRD susceptibility variant are consistent with the MRVCE model. The susceptibility polymorphisms of GABRD ...
    hmg.oxfordjournals.org/cgi/content/full/14/suppl_2/R243
  • Neurology Department at Vanderbilt
    Reduction of GABAA receptor function produces seizures and epilepsy in animals ... The delta subunit susceptibility variants E177A and R220H associated ...
    www.mc.vanderbilt.edu/neurology/faculty/macdonald.htm
  • Review
    A frequently occurring SNP, R220H in GABRD, which encodes the GABA. A ... LM, Feng HJ, Richards MC, et al. GABRD encoding. a protein for extra- or peri-synaptic ...
    qjmed.oxfordjournals.org/cgi/reprint/hcl021v1.pdf
  • Sacred disease secrets revealed: the genetics of human epilepsy
    In the same study, another variant, R220H, was. detected in a JME family, but it was also present in the ... (2004) GABRD encoding a protein for extra- or peri-synaptic GABAA ...
    www.lira.dist.unige.it/IIT_school/files/paper_Cossette.pdf
  • Arch Neurol -- Abstract: A Splice-Site Mutation in GABRG2 ...
    Archives of Neurology, a monthly professional medical journal published by the American Medical Association, publishes original, peer-reviewed scientific research on ...
    archneur.ama-assn.org/cgi/...&vol=59&fp=1137&view=short

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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