Re-evaluation of missense variant classifications in NF2

Area of Science:

• Genetics
• Genomic Medicine
• Molecular Biology

Background:

• Missense variants in the NF2 gene cause variable presentations of NF2 disease.
• Classifying the pathogenicity of NF2 missense variants is difficult due to limited functional and evidence-based data.

Purpose of the Study:

• To summarize NF2 missense variants and classify them based on available evidence.
• To investigate the distribution of NF2 missense variants across the gene and compare it with population data.

Main Methods:

• NF2 missense variants were collected from pathology databases and scientific literature.
• Variant classification followed the Association for Clinical Genomic Sciences Best Practice Guidelines (2020).
• Variant frequencies were analyzed across NF2 exons and compared between gnomAD population data and disease-associated variants.

Main Results:

• Most NF2 missense variants remain classified as variants of uncertain significance.
• NF2 variants from pathology databases showed varying rates of occurrence by exon, with the highest in exon 7.
• A potential genotype-phenotype correlation was suggested by differing variant frequencies between population and disease data.

Conclusions:

• Further phenotypic and functional data are required for definitive NF2 missense variant interpretation.
• Differences in variant distribution suggest a potential genotype-phenotype correlation in NF2 disease that warrants further investigation.