NM_198903.2(GABRG2):c.245G>A (p.Arg82Gln)

NM_198903.2(GABRG2):c.245G>A (p.Arg82Gln)

Variant type:
single nucleotide variant
Cytogenetic location:
5q34
Genomic location:
  • Chr5:162093965 (on Assembly GRCh38)
  • Chr5:161520971 (on Assembly GRCh37)
Protein change:
R43Q, R82Q
HGVS:
  • NG_009290.1:g.31324G>A
  • NM_000816.3:c.245G>A
  • NM_198903.2:c.245G>A
  • NC_000005.10:g.162093965G>A (GRCh38)
  • NP_000807.2:p.Arg82Gln
  • NP_944493.2:p.Arg82Gln
  • NC_000005.9:g.161520971G>A (GRCh37)
Links:
NCBI 1000 Genomes Browser:
rs121909673
Molecular consequence:
NM_198903.2:c.245G>A: missense variant [Sequence Ontology SO:0001583]

Clinical significance

NM_198903.2(GABRG2):c.245G>A (p.Arg82Gln)

Clinical significance:
Pathogenic, risk factor
Review status:
2 stars out of maximum of 4 stars
classified by multiple submitters
Number of submission(s):
2
Condition(s)
See supporting ClinVar records

1 Affected gene

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Recent activity

Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter - Study name
(Last submitted)
Submission accession
risk factor
(Jan 13, 2014)
classified by single submitter
(literature only)
literature onlygermlinePubMed (5)
[See all records that cite these PMIDs]
OMIM

(Dec 30, 2010)

SCV000037864
Pathogenic
(Jan 13, 2014)
classified by single submitter
(literature only)
literature onlygermlinePubMed (5)
[See all records that cite these PMIDs]
OMIM

(Dec 30, 2010)

SCV000037865

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermlinenot providednot provided

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

By in vitro functional expression assays in HEK293T cells, Kang et al. (2006) demonstrated that brief increases in temperature resulted in impaired trafficking, accelerated endocytosis, and decreased surface expression of heterozygous R43Q mutant GABA-alpha receptors. The findings provided an explanation for the triggering of seizures by fever in patients with the mutation.
Chaumont et al. (2013) found that R43Q gamma-2 subunits were retained within the endoplasmic reticulum of transfected COS-7 cells and rat hippocampal neurons. They also found mutant gamma-2 subunits in GABA-A receptors expressed at the cell surface. However, receptors with R43Q gamma-2 had a shorter residency time at the plasma membrane than their wildtype counterparts and were highly subject to internalization via a clathrin (see 118955)- and dynamin (see 602377)-dependent mechanism. Blockade of endocytosis led to a major increase in surface targeting of R43Q gamma-2. Using molecular modeling, Chaumont et al. (2013) found that R43 in gamma-2 resides at the gamma-2/beta-2 interface in the extracellular domain.
Sancar and Czajkowski (2004) found that the R43Q substitution in the gamma-2 subunit impaired cell surface expression of the subunit in transfected HEK293 cells. The substitution had no effect on GABA binding or GABA agonist-induced currents by alpha-1/beta-2 GABA-A receptors. However, lack of functional gamma-2 subunits in the complex abolished benzodiazepine binding and the ability of benzodiazepine to potentiate GABA agonist-induced currents.
Using coimmunoprecipitation analysis, Frugier et al. (2007) found that the R43Q substitution did not alter interaction of the gamma-2 subunit with alpha-3 or beta-3 subunits. However, the stoichiometry of the interactions was different than wildtype, and mutant gamma-2 did not colocalize at the cell surface with alpha-3 or beta-3 in transfected rat hippocampal neurons or transfected COS-7 cells. Mutation analysis revealed that R43 is a major determinant to drive cell surface targeting of the gamma-2 subunit.
Wallace et al. (2001) reported studies in a 4-generation family in which childhood absence epilepsy (ECA2; 607681) and febrile seizures (see 611277) occurring alone or in combination affected many members. They identified a heterozygous 245G-A transition in the GABRG2 cDNA leading to an arg43-to-gln (R43Q) substitution in the mature GABRG2 protein. The mutation abolished in vitro sensitivity to diazepam, raising the possibility that endozepines, in fact, exist and have a physiologic role in preventing seizures. Wallace et al. (2001) pointed out that the 2 syndromes, FS and CAE, have different ages of onset, and the physiology of absences and seizures is distinct. This suggested that the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes.

Last Updated: Oct 30, 2014