ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.6792C>A (p.Tyr2264Ter) (rs772295894)

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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 RCV000489640 SCV000885840 pathogenic not provided 2017-10-27 criteria provided, single submitter clinical testing The NF1 c.6855C>A; p.Tyr2285Ter variant (rs772295894), also known as c.6792C>A; p.Tyr2264Ter, induces an early termination codon and is predicted to result in a truncated protein or mRNA subjected to nonsense mediated decay. This variant is described as a recurrent variant associated with neurofibromatosis type 1, and studies have also shown it to cause exon skipping (Buske 1999, Hernandez-Imaz 2013, Robinson 1995, Sabbagh 2013, Wimmer 2007, Zhu 2016). This variant is reported as pathogenic in ClinVar (Variation ID: 185082), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Taken together, this variant is considered pathogenic. REFERENCES Buske A et al. Recurrent NF1 gene mutation in a patient with oligosymptomatic neurofibromatosis type 1 (NF1). Am J Med Genet. 1999 Oct 8;86(4):328-30. Hernandez-Imaz E et al. Characterization of NF1 allele containing two nonsense mutations in exon 37 that segregates with neurofibromatosis type 1. Clin Genet. 2013 May;83(5):462-6. Robinson PN et al. Two recurrent nonsense mutations and a 4 bp deletion in a quasi-symmetric element in exon 37 of the NF1 gene. Hum Genet. 1995 Jul;96(1):95-8. Sabbagh A et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013 Nov;34(11):1510-8. Wimmer K et al. Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption. Hum Mutat. 2007 Jun;28(6):599-612. Zhu L et al. Clinical and Molecular Characterization of NF1 Patients: Single-Center Experience of 32 Patients From China. Medicine (Baltimore). 2016 Mar;95(10):e3043.
Ambry Genetics RCV000164442 SCV000215082 pathogenic Hereditary cancer-predisposing syndrome 2015-05-21 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 RCV000489640 SCV000842896 pathogenic not provided 2017-11-03 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000199249 SCV000782087 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763393 SCV000894107 pathogenic Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000489640 SCV000576667 pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing The Y2264X nonsense variant in the NF1 gene has been reported previously in association with neurofibromatosis type 1 (Buske et al., 1999; Wimmer et al., 2007; Hernández-Imaz et al., 2013; Cali et al., 2016; Zhu et al., 2016). This variant has been reported de novo in at least one individual and segregated with disease in at least one large family (Hernandez-Imaz et al., 2013; Cali et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay, and has been shown to result in exon skipping (Wimmer et al., 2007; Hernández-Imaz et al., 2013). Additionally, the variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic.
Invitae RCV000199249 SCV000253829 pathogenic Neurofibromatosis, type 1 2018-12-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr2264*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic. This particular variant has been reported in the literature in many individuals affected with neurofibromatosis type 1 (PMID: 7607663, 9385374, 10607834, 12807981, 17311297, 26962827). Experimental studies have shown that this sequence change disrupts an exonic splicing enhancer in exon 45 (referred to as exon 37 in the literature), causing the in-frame skipping of exon 45 and the loss of amino acids 2253-2286 (PMID: 9385374, 9463322, 10607834, 16870183, 22925204). Additional experiments suggest that this sequence change will also cause the out-of-frame skipping of exons 44-45 (PMID: 16870183). For these reasons, this variant has been classified as Pathogenic.
Molecular Oncology Initiative,University of California, San Francisco RCV000851299 SCV000993589 pathogenic Ewing's sarcoma; Neurofibromatosis, type 1 2018-09-04 no assertion criteria provided clinical testing

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