ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.1270C>T (p.Arg424Cys)

gnomAD frequency: 0.00001  dbSNP: rs763826793
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000795518 SCV000934983 uncertain significance Neurofibromatosis, type 2 2023-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 424 of the NF2 protein (p.Arg424Cys). This variant is present in population databases (rs763826793, 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: 642120). 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 RCV002256506 SCV002528169 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-01 criteria provided, single submitter curation
Ambry Genetics RCV002256506 SCV002683735 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-16 criteria provided, single submitter clinical testing The p.R424C variant (also known as c.1270C>T), located in coding exon 12 of the NF2 gene, results from a C to T substitution at nucleotide position 1270. The arginine at codon 424 is replaced by cysteine, an amino acid with highly dissimilar properties. 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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