ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.1252C>T (p.Arg418Cys) (rs765540111)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000692241 SCV000820053 uncertain significance Neurofibromatosis, type 2 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 418 of the NF2 protein (p.Arg418Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs765540111, ExAC 0.01%). This variant has been observed in an individual affected with sporadic vestibular schwannoma (PMID: 8012353). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV001010549 SCV001170769 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing The p.R418C variant (also known as c.1252C>T), located in coding exon 12 of the NF2 gene, results from a C to T substitution at nucleotide position 1252. The arginine at codon 418 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in the germline in one individual with sporadic vestibular schwannoma who did not have a clinical diagnosis of NF2 and was not observed in 150 healthy controls (Jacoby LB et al. Hum. Mol. Genet., 1994 Mar;3:413-9). 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.

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