ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000012.11) (NC_000012.12)
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

- In terms of HI predictors, GRIN2B has a pLI score of 1 with an observed/expected ratio of 48.9 SNVs expected and 0 observed as of Sept 2019. - %HI is 10.82 from DECIPHER (in the higher ranks). The weight of these two predictive scores are in agreement -- this was considered as supporting evidence for HI and the probability of these loss-of-function intolerant scores suggests that GRIN2B haploinsufficiency is most likely not tolerated. In total, given the spectrum of genetic changes in GRIN2B along with additional reports of patients (e.g. >20) since previous curation with de novo loss of function variants, suggests a score of 3 for haploinsufficiency (and an aggregate score of 0.99 points or higher based on individual case ?evidence data from updated ClinGen scoring rubric) Several other reports described in HGMD (numerous to list all) with nonsense variants reported Grozeva (2015) Hum Mutat PMID: 26350204 Trujillano (2017) Eur J Hum Genet PMID: 27848944 Ch?rot (2018) Clin Genet PMID: 28708303

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Although larger duplications (over 50 genes affected) involving GRIN2B have been reported in a case study with neurodevelopmental anomalies (PMID 24503147), focal duplications of GRIN2B have not been reported.