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. 2022 May;43(5):643-654.
doi: 10.1002/humu.24370. Epub 2022 Apr 2.

Re-evaluation of missense variant classifications in NF2

Katherine V Sadler  1   2 , Charlie F Rowlands  1   2 , Philip T Smith  1 , Claire L Hartley  1 , Naomi L Bowers  1 , Nicola Y Roberts  1 , Jade L Harris  1 , Andrew J Wallace  1 , D Gareth Evans  1   2 , Ludwine M Messiaen  3 , Miriam J Smith  1   2
Affiliations

Re-evaluation of missense variant classifications in NF2

Katherine V Sadler et al. Hum Mutat. 2022 May.

Abstract

Missense variants in the NF2 gene result in variable NF2 disease presentation. Clinical classification of missense variants often represents a challenge, due to lack of evidence for pathogenicity and function. This study provides a summary of NF2 missense variants, with variant classifications based on currently available evidence. NF2 missense variants were collated from pathology-associated databases and existing literature. Association for Clinical Genomic Sciences Best Practice Guidelines (2020) were followed in the application of evidence for variant interpretation and classification. The majority of NF2 missense variants remain classified as variants of uncertain significance. However, NF2 missense variants identified in gnomAD occurred at a consistent rate across the gene, while variants compiled from pathology-associated databases displayed differing rates of variation by exon of NF2. The highest rate of NF2 disease-associated variants was observed in exon 7, while lower rates were observed toward the C-terminus of the NF2 protein, merlin. Further phenotypic information associated with variants, alongside variant-specific functional analysis, is necessary for more definitive variant interpretation. Our data identified differences in frequency of NF2 missense variants by exon between gnomAD population data and NF2 disease-associated variants, suggesting a potential genotype-phenotype correlation; further work is necessary to substantiate this.

Keywords: NF2; classification guidelines; missense; neurofibromatosis type 2; variant classification.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart outlining variant compilation
Figure 2
Figure 2
A comparison of rates of NF2 missense variants in gnomAD v2.1.1 (controls), all variants identified within this study, and NF2 disease‐associated variants. Rates were calculated as a percentage of the number of variants in comparison to exon size in amino acids. Assumed benign variation in the gnomAD v2.1.1 (controls) data set remains consistent across the gene. In contrast, there is an increased rate of variation in a number of exons for variants identified in pathology databases
Figure 3
Figure 3
NF2 isoform 1. Missense variants with corresponding classifications are labeled on the exon‐intron structure at the top of the figure. Confirmed NF2‐associated variants are tagged in red. Likely pathogenic and pathogenic variants are labeled with variant nomenclature. Exon boundaries are highlighted on a schematic of the translated protein product with annotated secondary structures, as well as the tertiary domains of the protein. NF2 transcript RefSeq NM_000268.4
See this image and copyright information in PMC

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