ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.1540A>G (p.Met514Val) (rs201527155)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000203209 SCV000258269 uncertain significance Neurofibromatosis, type 2 2015-06-19 criteria provided, single submitter clinical testing
Invitae RCV000203209 SCV000553674 uncertain significance Neurofibromatosis, type 2 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 514 of the NF2 protein (p.Met514Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs201527155, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with bilateral vestibular schwannomas (PMID: 16983642). ClinVar contains an entry for this variant (Variation ID: 201125). Experimental studies have shown that this missense change may destabilize the structure of the NF2 protein and disrupts its binding to the Lats1 protein (PMID: 26045165). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000565248 SCV000674131 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-08 criteria provided, single submitter clinical testing The p.M514V variant (also known as c.1540A>G), located in coding exon 14 of the NF2 gene, results from an A to G substitution at nucleotide position 1540. The methionine at codon 514 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in a patient with bilateral vestibular schwannomas (Ahronowitz I et al. Hum. Mutat., 2007 Jan;28:1-12). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics RCV000203209 SCV000839526 uncertain significance Neurofibromatosis, type 2 2018-07-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000203209 SCV001306002 benign Neurofibromatosis, type 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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