Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NF1 : obsolete neurofibromatosis, type 1

HGNC:7765 | MONDO_0008077
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: General Gene Curation
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10 8 11.5 10
Maruoka R et al. 2014 Nov (PMID:25325900); Kluwe L et al. 2003 May (PMID:12746402);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
Maruoka R et al. 2014 Nov (PMID:25325900); Kluwe L et al. 2003 May (PMID:12746402); Valero MC et al. 2011 Mar (PMID:21354044);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
Larribere L et al. 2015 Jul (PMID:25824590);
Non-patient cells 0.5 0 - 1 2 1.5
Larribere L et al. 2015 Jul (PMID:25824590); Ozawa T et al. 2005 Nov 25 (PMID:16169856);
Models Non-human model organism 2 0 - 4 4 2 4 4
Zhu Y et al. 2002 May 03 (PMID:11988578); Lee JS et al. 2010 Dec 01 (PMID:20858602);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
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.