ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4537C>T (p.Arg1513Ter) (rs760703505)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000255589 SCV000885838 pathogenic not provided 2017-05-16 criteria provided, single submitter clinical testing The NF1 c.4600C>T;p.Arg1534Ter (also known as c.4537C>T;p.Arg1513Ter) variant has been published in the medical literature in several individuals with a clinical diagnosis of NF1 (Fahsold 2000, Hutter 2016, Jeong 2006, Ko 2013, Side 1997, Valero 2011). The variant is listed in the ClinVar database (Variation ID: 220152) and the dbSNP variant database (rs760703505) with an allele frequency of 0.0008 percent in the Genome Aggregation Database. This variant introduces a premature termination codon, which is predicted to result in a truncated protein or absent transcript. Considering available information, this variant is classified as pathogenic. References: 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. Hutter S et al. No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients. Hum Genet. 2016 May;135(5):469-75. Jeong SY et al. The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J Korean Med Sci. 2006 Feb;21(1):107-12. Ko JM et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 2013 Jun;48(6):447-53. Side L et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med. 1997 Jun 12;336(24):1713-20. Valero MC et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011 Mar;13(2):113-22.
Ambry Genetics RCV000492716 SCV000581282 pathogenic Hereditary cancer-predisposing syndrome 2016-01-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Athena Diagnostics Inc RCV000255589 SCV000842891 pathogenic not provided 2017-12-14 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000206013 SCV000782027 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415187 SCV000492997 likely pathogenic Multiple cafe-au-lait spots; Thoracic scoliosis; Subcutaneous neurofibromas 2014-09-29 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000206013 SCV000692355 pathogenic Neurofibromatosis, type 1 2017-05-18 no assertion criteria provided clinical testing
GeneDx RCV000255589 SCV000322356 pathogenic not provided 2018-10-24 criteria provided, single submitter clinical testing The R1513X variant in the NF1 gene has been reported previously in association with neurofibromatosis, type 1 (Kluwe et al., 2003; Mattocks et al., 2004; Jeong et al., 2006). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1513X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic.
Invitae RCV000206013 SCV000260477 pathogenic Neurofibromatosis, type 1 2018-06-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1513*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This is a recurrent variant that has been reported in many unrelated individuals affected with neurofibromatosis type 1 (PMID: 9180088, 10712197, 16479075, 21354044, 23668869, 26969325). ClinVar contains an entry for this variant (Variation ID: 220152). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.

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