ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3826C>G (p.Arg1276Gly) (rs199474742)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233439 SCV000284445 likely pathogenic Neurofibromatosis, type 1 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1276 of the NF1 protein (p.Arg1276Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with neurofibromatosis 1 (NF1) in the literature (PMID: 15060124) and in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 68340). An experimental study has shown that this missense change dramatically increased affinity for H-ras protein and resulted in suppression of activated ras alleles (PMID: 8628317). The clinical significance of this finding is uncertain. This missense change is located at a functionally conserved arginine finger of the GAP-related domain of the NF1 protein (PMID: 16380919). Two different variants (c.3827G>C and c.3827G>A) altering the same amino acid residue (p.Arg1276Pro and p.Arg1276Gln) have been reported in individuals affected with NF1, and these variants caused reduced GAP-stimulated GTP hydrolysis activity (PMID: 9668168, 10712197), indicating that this residue may be critical for protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507203 SCV000604492 likely pathogenic not specified 2017-01-20 criteria provided, single submitter clinical testing
Medical Genomics Laboratory,Department of Genetics UAB RCV000233439 SCV000999182 pathogenic Neurofibromatosis, type 1 2019-06-05 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059192 SCV000090721 not provided not provided no assertion provided not provided

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