ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000015.9) (NC_000015.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17704776 Brems et al (2007) reported loss-of-function autosomal dominant mutations in SPRED1 associated with a neurofibromatosis 1-like phenotype, including several nonsense, two frameshift, and a splice donor site mutation.
19443465 Spurlock et al (2009) screened 85 patients with a mild NF1-like phenotype (Legius syndrome) for SPRED1 mutations. SPRED1 mutations were identified in 6 cases; 5 were novel and included 3 nonsense (R16X, E73X, R262X), 2 frameshift (c.1048_c1049 delGG, c.149_1152del 4 bp), and a single missense mutation (V44D). Short direct or inverted repeats detected immediately adjacent to some SPRED1 mutations may have led to the formation of the microdeletions and base pair substitutions

Haploinsufficiency phenotype comments:

Legius syndrome is an autosomal dominant disorder that shows some similarities to neurofibromatosis type I (NF1; 162200), which is caused by mutation in the neurofibromin gene; however, Legius syndrome is less severe. Individuals with Legius syndrome typically have multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. Legius syndrome is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. See GeneReviews for a complete clinical overview. For a recent review of loss of function mutations described and a SPRED1 mutation database, see Brems et al (2012, PMID: 22753041).

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