ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.614T>C (p.Met205Thr)

gnomAD frequency: 0.00002  dbSNP: rs747871414
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466594 SCV000553679 uncertain significance Neurofibromatosis, type 2 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 205 of the NF2 protein (p.Met205Thr). This variant is present in population databases (rs747871414, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 412210). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF2 protein function with a negative predictive value of 80%. 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.
Sema4, Sema4 RCV002257726 SCV002528200 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-08 criteria provided, single submitter curation
Ambry Genetics RCV002257726 SCV002654931 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-23 criteria provided, single submitter clinical testing The p.M205T variant (also known as c.614T>C), located in coding exon 7 of the NF2 gene, results from a T to C substitution at nucleotide position 614. The methionine at codon 205 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV000466594 SCV004825349 uncertain significance Neurofibromatosis, type 2 2023-05-04 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 205 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with NF2-related disorders in the literature. This variant has been identified in 3/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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