ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.770C>T (p.Pro257Leu)

gnomAD frequency: 0.00001  dbSNP: rs753300935
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000806949 SCV000946973 uncertain significance Neurofibromatosis, type 2 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 257 of the NF2 protein (p.Pro257Leu). This variant is present in population databases (rs753300935, gnomAD 0.003%). 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: 651559). 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.
Ambry Genetics RCV002397647 SCV002674443 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-12 criteria provided, single submitter clinical testing The p.P257L variant (also known as c.770C>T), located in coding exon 8 of the NF2 gene, results from a C to T substitution at nucleotide position 770. The proline at codon 257 is replaced by leucine, 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 RCV000806949 SCV004827689 uncertain significance Neurofibromatosis, type 2 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 257 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 2/251476 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.
Baylor Genetics RCV004569640 SCV005052378 uncertain significance Familial meningioma 2023-12-15 criteria provided, single submitter clinical testing

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