Submissions for variant NM_001134407.3(GRIN2A):c.1943A>G (p.Asn648Ser)

dbSNP: rs796052545

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187638	SCV000241235	uncertain significance	not provided	2014-02-12	criteria provided, single submitter	clinical testing	p.Asn648Ser (AAT>AGT): c.1943 A>G in exon 10 of the GRIN2A gene (NM_000833.3). The N648S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a conserved position in the ligand-gated ion channel domain of the GRIN2A protein. Missense variants in nearby residues, F652V and L649V, have been reported as de novo mutations in an individual with CSWSS (Lesca et al., 2013) and in an individual with severe intellectual disability and epilepsy (de Ligt et al., 2012), respectively, supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the N648S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Institute of Human Genetics, University of Leipzig Medical Center	RCV001781548	SCV002026449	likely pathogenic	Landau-Kleffner syndrome	2019-01-01	criteria provided, single submitter	research