ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.6246del (p.Arg2083fs)

dbSNP: rs1597842843
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002167 SCV001160026 pathogenic not specified 2018-10-10 criteria provided, single submitter clinical testing The NF1 c.6246delA; p.Arg2083fs variant, to our knowledge, is not described in the medical literature or in gene-specific databases. It is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in association with neurofibromatosis type 1 and are considered pathogenic (Bianchessi 2015, Fahsold 2000, Sabbagh 2013). Based on available information, the p.Arg2083fs variant is considered pathogenic. REFERENCES Bianchessi D et al. 126 novel mutations in Italian patients with neurofibromatosis type 1. Mol Genet Genomic Med. 2015 Jul 7;3(6):513-25. Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Sabbagh A et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013 Nov;34(11):1510-8.
Labcorp Genetics (formerly Invitae), Labcorp RCV003598014 SCV004427024 pathogenic Neurofibromatosis, type 1 2022-12-31 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 811798). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2062Alafs*4) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538).

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