ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.495_498TGTT[1] (p.Cys167fs) (rs786201874)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164374 SCV000215009 pathogenic Inborn genetic diseases 2014-06-06 criteria provided, single submitter clinical testing
Invitae RCV000461491 SCV000542062 pathogenic Neurofibromatosis, type 1 2020-01-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys167Glnfs*10) 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 variant has been reported as a recurrent mutation in individuals with neurofibromatosis type 1 (PMID: 10543400, 24294391, 17726231, 17311297, 27838393). It is also known as 495delTGTT in the literature. 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 RCV000486687 SCV000568598 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing This deletion of 4 nucleotides in NF1 is denoted c.499_502delTGTT at the cDNA level and p.Cys167GlnfsX10 (C167QfsX10) at the protein level. The normal sequence, with the bases that are deleted in braces, is TGTT[TGTT]CAGA. The deletion causes a frameshift which changes a Cysteine to a Glutamine at codon 167, and creates a premature stop codon at position 10 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously published as NF1 495delTTGT, has been observed in multiple individuals with a clinical diagnosis of Neurofibromatosis Type 1 (Osborn 1999, Ars 2003, Lee 2006, Bendova 2007, Brinckmann 2007, Wimmer 2007, Sabbagh 2013, Schaefer 2013, Uusitalo 2014). Pasmant et al. (2011) identified this variant in an individual whose malignant peripheral nerve sheath tumor displayed loss of heterozygosity. We consider this variant to be pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000461491 SCV000781872 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital RCV001009588 SCV001169689 pathogenic Neurofibromatosis, type 1; Tibial pseudoarthrosis 2018-11-10 criteria provided, single submitter research
Ambry Genetics RCV001023375 SCV001185242 pathogenic Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing The c.499_502delTGTT variant, located in coding exon 5 of the NF1 gene, results from a deletion of 4 nucleotides at nucleotide positions 499 to 502, causing a translational frameshift with a predicted alternate stop codon (p.C167Qfs*10). This mutation has been observed in multiple patients with sporadic or familial NF1 diagnoses (Osborn MJ and Upadhyaya M. Hum. Genet. 1999 Oct;105:327-32; Toliat MR et al. Electrophoresis. 2000 Feb;21:541-4; Ars E et al. J. Med. Genet. 2003 Jun;40:e82; Schaefer IM et al. Int J Clin Exp Pathol, 2013 Nov;6:3003-8; Uusitalo E et al. Acta Derm. Venereol., 2014 Nov;94:663-6; Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60). 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.
Medical Genetics, University of Parma RCV000461491 SCV001218909 pathogenic Neurofibromatosis, type 1 2019-12-20 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000461491 SCV001369727 pathogenic Neurofibromatosis, type 1 2019-12-05 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000461491 SCV000692336 pathogenic Neurofibromatosis, type 1 2014-07-15 no assertion criteria provided clinical testing

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