Submissions for variant NM_000834.5(GRIN2B):c.2002G>T (p.Asp668Tyr)

dbSNP: rs876661151

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221616	SCV000279671	likely pathogenic	not provided	2015-11-25	criteria provided, single submitter	clinical testing	The D668Y variant in the GRIN2B gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D668Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D668Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. The D668Y variant is a strong candidate for a pathogenic variant.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001172320	SCV001335342	likely pathogenic	Intellectual disability, autosomal dominant 6	2017-04-04	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
Labcorp Genetics (formerly Invitae), Labcorp	RCV005222844	SCV005865166	pathogenic	Intellectual disability, autosomal dominant 6; Developmental and epileptic encephalopathy, 27	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 668 of the GRIN2B protein (p.Asp668Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 28377535). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 234668). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GRIN2B protein function with a positive predictive value of 95%. This variant disrupts the p.Asp668 amino acid residue in GRIN2B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34160719; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.