NF1

Gene Facts

• HGNC Symbol: NF1 (HGNC:7765)
• HGNC Name: neurofibromin 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: No aliases found
• %HI: 0.88
• pLI: 1
• LOEUF: 0.45
• Cytoband: 17q11.2
• Genomic Coordinates:

  GRCh37/hg19:	chr17:29421945-29704695
  GRCh38/hg38:	chr17:31094927-31377677

• MANE Select Transcript: NM_001042492.3 ENST00000358273.9
• Function: Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity. {ECO:0000269|PubMed:2121371, ECO:0000269|PubMed:8417346}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-3802
• ClinGen Curation ID: CCID:007547
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Related Links:
  17q11.2 recurrent region (includes NF1)
• Last Evaluated: 02/12/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• neurofibromatosis type 1

HI Evidence

• PUBMED: 1757093
  Estivill et al (1991) analyzed exon 4 of the NF1 gene in 38 patients with NF1. In one patient, they found a de novo nonsense mutation (R365X). Other groups also reported this mutation in NF1 patients.
• PUBMED: 1302608
  Upadhyaya et al. (1992) analyzed the NF1 gene in 200 patients with NF1. They found multiple mutations, including a single bp insertion resulting in a frameshift and premature stop codon in two unrelated patients.
• PUBMED: 34427956
  Riva et al (2022), in Genes Chromosomes Cancer) reviewed records from January 2000 to December 2019. Genetic testing was performed on patients having a clinical suspicion of Neurofibromatosis type I based on the presence of at least two of the clinical manifestations proposed by the National Institute of Health Consensus Development Conference, that is, the presence of six or more CALs > 15 mm in adults and > 5 mm in children Analyses was performed on genomic DNA were conducted using denaturing high pressure liquid chromatography (DHPLC) and sequencing of samples with a profile difference from a wild‐type control, whereas, starting from June 2016, the laboratory has switched to NGS using the Illumina MiSeq platform The authors found 2 patient with a gross deletion of NF1, 12 patients w/ nonsense variants, 11 indel frameshift causing variants, 8 splice site variants, no missense alterations.
• PUBMED: 34750850
  La-Salle et al (2022) performed sequential gene sequencing by Sanger method or next generation sequencing (NGS) with a multigene panel in a Canadian cohort. They note NF1, RET and VHL as genes known to predispose individuals to PHEOs w/ AD transmission. They found 2 affected patients with variants in NF1, one of them being a pathogenic deletion of the entire coding sequence (Table 2 in publication).
• PUBMED: 28230061
  Gutmann et al (Nature Reviews 2017) cataloged and reviewed a large set of different germline NF1 variants of clinical importance resulting in loss or reduced function of protein. Although genotype–phenotype correlations are uncommon in neurofibromatosis type 1, three well-established correlations were identified. Individuals with 1.4 Mb deletions that encompass the entire NF1 gene typically show facial dysmorphism, reduced intellectual abilities and an increased incidence of cancer. In addition, ∼1% of people with neurofibromatosis type 1 have mutations that affect codon 1809 and typically present with café-au-lait macules (CALMs), short stature and pulmonic stenosis, but lack externally visible plexiform or dermal neurofibromas.

• HI Evidence Comments: Loss of function variants and deletions of NF1 are associated with neurofibromatosis 1. NF1 has a definitive association for Neurofibromatosis type 1 and hereditary pheochromoctomas , paraganglioma, has moderate gene disease associated for myoyamoya disease (GenCC, accessed 2.2023). Variants in NF1 were first reported in humans with this disease as early as 1990 (Wallace et al., PMID 2134734). Diagnosis of Neurofibromatous Type 1 is based on criteria established by the NIH (1988; PMID 3152465). At least 3000 unique germline variants have been identified (reviewed in Gutmann et al., 2017; PMID 28230061). This gene-disease relationship is well-known and therefore a significant amount of case-level data, segregation data and experimental data is available in the literature, See Gene Reviews for additional mutations. https://www.ncbi.nlm.nih.gov/books/NBK1109/

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Focal duplications of NF1 not readily reported or known to demonstrate dosage sensitivity Grisart et al (2008, PMID: 18183042) in Eur J Hum Genetics reported seven members of a family with a 1.5-Mb microduplication corresponding to the type I NF1 microdeletion region within 17q11. These were analyzed by array CGH , 44k Agilent microarray. Main phenotypic features from this study were ID, early onset of baldness (15 years old), dental enamel hypoplasia and minor facial dysmorphism. The authors remark that it cannot be fully ruled out whether the origin of the phenotype observed in this family is linked to the NF1 microduplication or an environmental/unidentified genetic origin. Moles et al. (2012) (PMID 22241097) reported 7 individuals with microduplications involving NF1 (along with several other genes). The phenotypes of the patients are variable, including DD/ID and seizures. These duplications are mediated by NAHR and have been reported by another group (Grisart 2008 EJHG). The microduplication region is ~1.4 Mb and includes at least 10 genes.