ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.240+1G>A

dbSNP: rs587776562
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001237903 SCV001410690 pathogenic Neurofibromatosis, type 2 2023-12-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the NF2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with neurofibromatosis type 2 (PMID: 7913580, 8379998, 29409008; Invitae). ClinVar contains an entry for this variant (Variation ID: 963818). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003414039 SCV004109920 pathogenic NF2-related disorder 2023-05-02 criteria provided, single submitter clinical testing The NF2 c.240+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in an individual with neurofibromatosis type 2 (Table S6 - Louvrier et al. 2018. PubMed ID: 29409008). Additionally, different nucleotide substitutions affecting this site (c.240+1G>C and c.240+1G>T) have been reported as pathogenic (MacCollin et al. 1994. PubMed ID: 7913580; Table S1 - Ahronowitz et al. 2007. PubMed ID: 16983642; Table S6 - Louvrier et al. 2018. PubMed ID: 29409008). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/963818/). Variants that disrupt the consensus splice donor site in NF2 are expected to be pathogenic. This variant is interpreted as pathogenic.
All of Us Research Program, National Institutes of Health RCV001237903 SCV005431269 likely pathogenic Neurofibromatosis, type 2 2024-06-09 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +1 position of intron 2 of the NF2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with neurofibromatosis type 2 (PMID: 34285798). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.240+1G>C and c.240+1G>T, are known to be disease-causing (ClinVar Variation ID: 848788, 3283). Loss of NF2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

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