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NM_000682.7(ADRA2B):c.675_686delinsGTTTGGCAG (p.His225_Leu229delinsGlnPheGlyArg) AND Epilepsy, familial adult myoclonic 2

Significance: Uncertain significance
ClinVar: RCV000172992

Variant: NM_000682.7(ADRA2B):c.675_686delinsGTTTGGCAG (p.His225_Leu229delinsGlnPheGlyArg)

Type: Variant
Allele: NM_000682.7(ADRA2B):c.675_686delinsGTTTGGCAG (p.His225_Leu229delinsGlnPheGlyArg) 190153
Gene:
Type: Indel
Location: Chr2: 96115464 - 96115475 - assembly GRCh38
Chr2: 96781203 - 96781214 - assembly GRCh37
References: dbSNP: 879255577
OMIM: 104260.0001

Condition

Disease: Epilepsy, familial adult myoclonic 2

Citations

    In affected members of the families with FAME2 reported by De Fusco et al. (2014) and Guerrini et al. (2001), Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene (616712.0001). The findings suggested that the ADRA2B allele is not causative.
PMID:11701600
    In affected members of 2 large multigenerational Italian families with familial adult myoclonic epilepsy-2 (FAME2; 607876), De Fusco et al. (2014) identified a heterozygous in-frame insertion/deletion (c.675_686del/ins), resulting in the substitution of 5 amino acids (HGGAL) with 4 new residues (QFGR) (H225_L229delinsQ225_F_G_R228). The variant, which was found by sequencing genes in the candidate region on chromosome 2p1.1-q1.2 identified by linkage analysis (Guerrini et al., 2001), segregated with the disorder in the families. It was not found in the dbSNP, Exome Variant Server, and 1000 Genomes Project databases, or in 575 unrelated controls from Tuscany. Haplotype analysis suggested a founder effect. The variant occurred in the third intracellular loop, a crucial conserved domain for receptor localization and signal transduction. In vitro functional expression assays in cells and Xenopus oocytes showed that the variant interfered with receptor binding to the scaffolding protein spinophilin (PPP1R9B; 603325) upon neurotransmitter activation, thus resulting in increased epinephrine-stimulated calcium signaling, consistent with a gain of function.
PMID:11701600
    This variant, formerly titled EPILEPSY, FAMILIAL ADULT MYOCLONIC, 2 based on the report of De Fusco et al. (2014), has been reclassified based on the report of Corbett et al. (2019).
PMID:24114805
    In affected members of the families with FAME2 reported by De Fusco et al. (2014) and Guerrini et al. (2001), Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene (616712.0001). The findings suggested that the ADRA2B allele is not causative.
PMID:24114805
    In affected members of 2 large multigenerational Italian families with familial adult myoclonic epilepsy-2 (FAME2; 607876), De Fusco et al. (2014) identified a heterozygous in-frame insertion/deletion (c.675_686del/ins), resulting in the substitution of 5 amino acids (HGGAL) with 4 new residues (QFGR) (H225_L229delinsQ225_F_G_R228). The variant, which was found by sequencing genes in the candidate region on chromosome 2p1.1-q1.2 identified by linkage analysis (Guerrini et al., 2001), segregated with the disorder in the families. It was not found in the dbSNP, Exome Variant Server, and 1000 Genomes Project databases, or in 575 unrelated controls from Tuscany. Haplotype analysis suggested a founder effect. The variant occurred in the third intracellular loop, a crucial conserved domain for receptor localization and signal transduction. In vitro functional expression assays in cells and Xenopus oocytes showed that the variant interfered with receptor binding to the scaffolding protein spinophilin (PPP1R9B; 603325) upon neurotransmitter activation, thus resulting in increased epinephrine-stimulated calcium signaling, consistent with a gain of function.
PMID:24114805
    This variant, formerly titled EPILEPSY, FAMILIAL ADULT MYOCLONIC, 2 based on the report of De Fusco et al. (2014), has been reclassified based on the report of Corbett et al. (2019).
PMID:31664034
    In affected members of the families with FAME2 reported by De Fusco et al. (2014) and Guerrini et al. (2001), Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene (616712.0001). The findings suggested that the ADRA2B allele is not causative.
PMID:31664034