ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3610C>G (p.Arg1204Gly)

dbSNP: rs199474732
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000059189 SCV000490665 pathogenic not provided 2021-08-10 criteria provided, single submitter clinical testing Published functional studies support a damaging effect: significant reduction in GTPase activity and mild reduction of interaction with SPRED1 (Thomas 2012, Hirata 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26635368, 22807134, 31766501, 25486365, 31370276, 27322474, 23447461, 10336779, 10712197, 24803665, 26633542)
Invitae RCV000632346 SCV000753524 pathogenic Neurofibromatosis, type 1 2020-03-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1204 of the NF1 protein (p.Arg1204Gly). The arginine residue is moderately 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 the literature many individuals affected with neurofibromatosis type 1 (PMID: 10336779, 26635368, 27322474, Invitae) and at least two of them arose de novo (PMID: 27322474, Invitae). ClinVar contains an entry for this variant (Variation ID: 68337). Experimental data suggest that this sequence change affects protein function by causing a significantly elevated level of activated GTP-bound Ras as compared to the wild type NF1 protein (PMID: 22807134). Activating sequence changes of Ras proteins may result in constitutive signaling, thereby stimulating cell proliferation and inhibiting apoptosis (PMID: 11459867). For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000632346 SCV000899247 pathogenic Neurofibromatosis, type 1 2019-04-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV001020722 SCV001182235 pathogenic Hereditary cancer-predisposing syndrome 2019-03-19 criteria provided, single submitter clinical testing The p.R1204G variant (also known as c.3610C>G), located in coding exon 27 of the NF1 gene, results from a C to G substitution at nucleotide position 3610. The arginine at codon 1204 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified an individual meeting NF1 diagnostic criteria (Krkljus S et al. Hum. Mutat., 1998;11:411). This variant has also been detected de novo in multiple unrelated individuals with NF1 (Hirata Y et al. J. Biol. Chem., 2016 Feb;291:3124-34). Experimental studies indicate that this variant will disrupt protein function (Thomas L et al. Hum. Mutat., 2012 Dec;33:1687-96). A different alteration at the same amino acid position, p.R1204W, has been identified in an individual meeting NF1 diagnostic criteria (Ars E et al. Hum. Mol. Genet., 2000 Jan;9:237-47). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this variant is classified as a pathogenic mutation.
Genome Diagnostics Laboratory,The Hospital for Sick Children RCV000632346 SCV001479235 pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000059189 SCV001879392 likely pathogenic not provided 2020-09-22 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least two individuals with clinical features associated with this gene, with one of those appearing to occur de novo. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show a reduction in activity of the GAP-related domain of NF1 (PMID: 22807134, 26635368). Computational tools predict that this variant is damaging.
Genome-Nilou Lab RCV000632346 SCV002559975 likely pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059189 SCV000090718 not provided not provided no assertion provided not provided
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000059189 SCV001956904 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000059189 SCV001967662 pathogenic not provided no assertion criteria provided clinical testing

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