ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.1563A>G (p.Ile521Met)

dbSNP: rs2147108932
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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 RCV002049430 SCV002117480 uncertain significance Neurofibromatosis, type 2 2021-10-24 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces isoleucine with methionine at codon 521 of the NF2 protein (p.Ile521Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NF2-related conditions. 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.
All of Us Research Program, National Institutes of Health RCV002049430 SCV004835617 uncertain significance Neurofibromatosis, type 2 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with methionine at codon 521 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 not been identified 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.
Ambry Genetics RCV004945728 SCV005457244 uncertain significance Hereditary cancer-predisposing syndrome 2024-11-11 criteria provided, single submitter clinical testing The p.I521M variant (also known as c.1563A>G), located in coding exon 14 of the NF2 gene, results from an A to G substitution at nucleotide position 1563. The isoleucine at codon 521 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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