Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NF2 : neurofibromatosis type 2

HGNC:7773 | MONDO_0007039
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 6
MacCollin M et al. 1994 Aug (PMID:7913580);
Proband with predicted or proven null variant 1.5 0-2 10 3 4 4
MacCollin M et al. 1994 Aug (PMID:7913580);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
MacCollin M et al. 1994 Aug (PMID:7913580); Parry DM et al. 1996 Sep (PMID:8751853);
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 1.5 1.5  
Candidate gene sequencing 7.19 3
MacCollin M et al. 1994 Aug (PMID:7913580); Parry DM et al. 1996 Sep (PMID:8751853);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 7.19    
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 1 0.5
Gutmann DH et al. 1995 Mar (PMID:7795605);
Functional Alteration Patient cells 1 0 - 2 2 1
James MF et al. 2009 Aug (PMID:19451225);
Non-patient cells 0.5 0 - 1 1 0.5
Fernandez-Valle C et al. 2002 Aug (PMID:12118253);
Models Non-human model organism 2 0 - 4 4 4 8 4
McClatchey AI et al. 1997 May 15 (PMID:9171370); McClatchey AI et al. 1998 Apr 15 (PMID:9553042); Giovannini M et al. 2000 Jul 01 (PMID:10887156); Gehlhausen JR et al. 2015 Jan 01 (PMID:25113746);
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 1 2
Poulikakos PI et al. 2006 Sep 28 (PMID:16652148);
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 first report indicating a relationship of the NF2 gene with autosomal dominant Neurofibromatosis type 2 was reported by Rouleau et al., 1993 (PMID: 8379998), albeit neurofibromatosis (subtypes not defined) was a widely recognized pathologic clinical entity in the late 19th century (Ahn et al., 1994; PMID: 25996397). Neurofibromatosis type 2 is characterized by the formation of benign bilateral or unilateral tumors (schwannomas, meningiomas, gliomas, and/or neurofibromas) in the central nervous, most commonly on the eighth cranial nerve (reviewed on Current evidence suggests a prevalence of Neurofibromatosis type 2 of 1 in 25,000 ( Numerous variants have been reported, in both ClinVar and in LOVD ( Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship has been studied for more than 20 years, therefore a significant amount of case-level data, segregation data, and experimental data is available and the maximum score for genetic evidence (12 points) and experimental evidence (6 points) 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 the gene-disease relationship is protein loss of function, as the NF2 protein product, termed Merlin or Schwannomin, is a tumor suppressor protein (Trofatter et al., 1993; PMID: 8453669). NF2 tumor suppressor function is regulated by the protein confirmation, with the closed form acting as the active tumor suppressor form (reviewed in Cooper and Giancotti, 2014 PMID:24726726). NF2 has been associated with multiple disease entities and/or phenotypes, including: (1) Meningioma, NF2-related, somatic (MIM: 607174) (2) Schwannomatosis, somatic Of note, these other phenotypes are noted as somatic, and therefore are not represented/ counted in this gene-disease relationship, and will be assessed separately. In summary, NF2 is DEFINITIVELY associated with autosomal dominant Neurofibromatosis Type 2. 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.