ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs765540111
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000692241 SCV000820053 uncertain significance Neurofibromatosis, type 2 2024-01-18 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 418 of the NF2 protein (p.Arg418Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sporadic vestibular schwannoma (PMID: 8012353). ClinVar contains an entry for this variant (Variation ID: 571182). 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 RCV001010549 SCV001170769 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-18 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 neurofibromatosis type 2 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 well 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.
Genome-Nilou Lab RCV000692241 SCV002044882 uncertain significance Neurofibromatosis, type 2 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV001010549 SCV002528168 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-25 criteria provided, single submitter curation
GeneDx RCV002280136 SCV002568561 uncertain significance not provided 2022-08-26 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8566958, 8757035, 30306255, 17134719, 16324214, 22482125, 8012353)
Baylor Genetics RCV003459687 SCV004199052 uncertain significance Familial meningioma 2023-08-02 criteria provided, single submitter clinical testing

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