ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3916C>T (p.Arg1306Ter) (rs376576925)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457194 SCV000542202 pathogenic Neurofibromatosis, type 1 2020-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1306*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This particular variant has been reported in many individuals affected with neurofibromatosis type 1 (PMID: 9783703, 16944272, 15146469, 16835897, 10712197, 26969325). ClinVar contains an entry for this variant (Variation ID: 404592). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000489457 SCV000577115 pathogenic not provided 2019-01-10 criteria provided, single submitter clinical testing The R1306X nonsense variant has been reported previously in association with neurofibromatosis type 1 (Griffiths et al., 2007; Laycock-van et al., 2011; Hutter et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we consider this variant to be pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000457194 SCV000782006 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000489457 SCV000927881 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000457194 SCV001156511 pathogenic Neurofibromatosis, type 1 2020-02-03 criteria provided, single submitter clinical testing
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital RCV001009594 SCV001169695 pathogenic Neurofibromatosis, type 1; Tibial pseudoarthrosis 2018-11-10 criteria provided, single submitter research
Ambry Genetics RCV001021430 SCV001183047 pathogenic Hereditary cancer-predisposing syndrome 2019-02-23 criteria provided, single submitter clinical testing The p.R1306* pathogenic mutation (also known as c.3916C>T), located in coding exon 29 of the NF1 gene, results from a C to T substitution at nucleotide position 3916. This changes the amino acid from an arginine to a stop codon within coding exon 29. This mutation has been detected in several individuals, once as a de novo occurrence, meeting NIH diagnostic criteria for Neurofibromatosis type 1 (NF1) (Marwaha A et al. Br. J. Dermatol., 2018 Nov;179:1216-1217, Tsipi M et al. J. Neurol. Sci., 2018 Dec;395:95-105).Park VM et al. J. Med. Genet., 1998 Oct;35:813-20; Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; Lee MJ et al. Hum Mutat. 2006 Aug;27(8):832; Hutter S et al. Hum Genet. 2016 May;135(5):469-75). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000457194 SCV001431876 pathogenic Neurofibromatosis, type 1 2020-08-31 criteria provided, single submitter clinical testing Variant summary: NF1 c.3916C>T (p.Arg1306X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251422 control chromosomes. c.3916C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (Fahsold_2000, Sabbagh_2013). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathongenic n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000489457 SCV001470147 pathogenic not provided 2020-05-14 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Athena Diagnostics Inc RCV000489457 SCV001476707 pathogenic not provided 2020-05-14 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000457194 SCV001479008 pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000489457 SCV001746524 pathogenic not provided 2021-05-01 criteria provided, single submitter clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000457194 SCV001190825 uncertain significance Neurofibromatosis, type 1 2020-02-05 no assertion criteria provided clinical testing

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