ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000022.10) (NC_000022.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
7913580 MacCollin et al. (1994): Describes 33 unrelated individuals with a clinical diagnosis of NF2. Of 20 unique variants observed, 19 were predicted to result in truncated protein due to frameshift, creation of a stop codon, or interference with normal RNA splicing, including 9 different nonsense mutations.
9817927 Zucman-Rossi et al (1998): Describes 19 unrelated individuals with a clinical diagnosis of NF2, six of whom were found to have either whole-gene or intragenic deletions of the NF2 gene.
11159946 Bruder et al. (2001): Describes deletions identified by arrayCGH involving NF2 identified in 17 additional previously unreported individuals with neurofibromatosis type 2. These cases include both intragenic deletions and larger deletions involving other genes.

Haploinsufficiency phenotype comments:

Loss-of-function mutations in NF2 have been associated with neurofibromatosis type 2. Of note, larger deletions encompassing the NF2 gene (in addition to other genes) have been described in patients with neurofibromatosis type 2, developmental delays and other congenital anomalies (as in PMID: 10338003). However, it has been suggested that whole-gene or intragenic deletions involving NF2 alone are associated with a milder NF2 phenotype than individuals with other types of mutations (GeneReviews; PMID:15190457). A meta-analysis by Ahronowitz et al. (PMID:16983642?summarized over 900 NF2 pathogenic variants reported prior to the year 2006. The mutation spectrum for constitutional alternations was 39% nonsense, 27% frameshift, 25% splicing site and 7% nontruncating; The mutation spectrum for somatic alternations was 56% frameshift, 19% nonsense, 19% splice site and 0% nontruncating. Currently in ClinVar (accessed on Sept. 7 2020), there are a total of 142 NF2 pathogenic or likely pathogenic variants including 31 frameshift, 30 nonsense, 27 splicing site, 24 exonic deletion and 8 missense variants. Recently, Evans et al. (PMID:31273341) reported a high prevalence of mosaic NF2 mutations among de novo NF2 cases. Among 232 confirmed mosaic patients, there were 97 nonsense, 57 frameshift, 32 CNV, 24 splicing site and 12 nontruncating variants. Overall the vast majority of NF2 pathogenic variants are loss-of-function variants which several hundreds had been reported.

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

Triplosensitivity phenotype comment:

Though intragenic duplications have been reported (as in PMID:15857181 and 15645494) in individuals with NF2, no whole-gene duplications of NF2 have been reported at this time.