ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
23160955 O'Roak et al. (2012): Report four different mutations in the GRIN2B gene, a frameshift, missense, nonsense, and splice-site. Probands were screened through exome sequencing of 44 ASD candidate genes in the Simons Simplex Collection (SSC). The mutations present in GRIN2B were de novo. The proband with the frameshift mutation (p.Ser34GlnfsX25) as well as the proband with the nonsense mutation (p.Trp559X) have a diagnosis of autism. No other phenotypic information was reported on these probands.
20890276 Endele et al. 2010 describe a de novo heterozygous deletion on exon 3 (c.803_804delCA) resulting in a frameshit mutation (p.T268SfsX15) in a female proband of German descent. She presented with moderate intellectual disability but no other phenotypic information was recorded. There were also two translocations and three missense mutations in the study. Freunscht et al. 2013 (PMID:23718928): Further describes the phenotype of the proband which carries the heterozygous deletion on exon 3. [This mutation was first described by Endele et al. (2010)] This proband exhibited global developmental delay, at age 12 had moderate intellectual disability. At age 13, she exhibited excessive talking while avoiding both physical and eye contact. She also has normal proportions and no dysmorphic features and exhibited stereotypic behaviors and echolalia.
28377535 Platzer et al., in Journal of Med Genet (2017) reported on one of the largest series review of GRIN2B-related neurodevelopmental disorders. Molecular testing was performed either by way of panels, WES, or aCGH. A total of 21 heterozygous de novo pathogenic variants in GRIN2B were identified leading to truncation/haploinsufficiency among different patients (see Table 2), all with developmental delay, severe to mild intellectual disability, ASD in a quarter of the patients, and epileptic spasms. These pathogenic variants (classified according to ACMG criteria) comprised of 11 nonsense/frameshift, 3 splice site, 4 gross deletions of only GRIN2B, and 3 chromosomal rearrangements. And all (likely) pathogenic missense variants cluster within proximity to ligand-binding sites of GRIN2B protein. In addition to these multiple pathogenic variants, several recurrent ones were also identified ((e.g., p.(Arg540His), p.(Gly689Ser), p.(Arg696His), p.(Ile751Thr) p.(Gly820Ala)) among patients with neurodevelopmental phenotypes. Of note, another recurrent variant c.99dupC, p.(Ser34Glnfs*25) listed in ExAC (not in gnomAD) was observed within a homopolymer stretch, suggesting a technical artifact. Overall the authors conclude that pathogenic variants in GRIN2B-related neurodevelopmental disorders appear to be a recurrent diagnosis implicated for this gene.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.