Submission Details

The relationship between NF1 and Neurofibromatosis Type 1 (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of February 26th, 2019. 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, therefore the maximum score for both genetic evidence and experimental evidence has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. In particular, earlier compelling evidence suggestive of the gene-disease relationship, such as linkage data, may not be reflected in the current curation. The mechanism for disease is likely loss of function as NF1 encodes neurofibromin, which regulates cell growth and survival through downstream signaling pathways and loss of nuerofibromin is predicted to lead to increased cell growth (reviewed in Gutmann et al., 2017; PMID 28230061). Of note, this gene has also been implicated in familial spinal Neurofibromatosis, Neurofibromatosis-Noonan syndrome, Watson syndrome and juvenile myelomonocytic leukemia (AD). NF1 patients with features more consistent with Noonan syndrome in addition to Neurofibromatosis Type 1 have been described as having Neurofibromatosis-Noonan syndrome (Baralle et al., 2003; PMID 12707950, De Luca et al., 2005; PMID 16380919, Stevenson et al., 2006; PMID 16542390, Chen et al., 2014; PMID 25049390). However, after further review of the phenotypes described in these patients, the ClinGen RASopathy Expert Panel has decided that these presentations are consistent with what would be expected in patients with NF1 Neurofibromatosis Type 1. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability for the disease entities mentioned and therefore they have been lumped into one disease entity, Neurofibromatosis Type 1. In summary, NF1 is definitively associated with autosomal dominant Neurofibromatosis Type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on February 27, 2019.