ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4084C>T (p.Arg1362Ter) (rs137854560)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000483061 SCV000885837 pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing The NF1 c.4084C>T; p.Arg1362Ter variant (rs137854560) is reported in the medical literature in individuals with neurofibromatosis type I (Fahsold 2000, Messiaen 2000, Upadhyaya 1997). The variant is listed in the ClinVar database (Variation ID: 344) as pathogenic by several sources. This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. 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. Messiaen LM et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15(6):541-55. Upadhyaya M et al. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. Hum Genet. 1997 Jan;99(1):88-92.
Ambry Genetics RCV000492495 SCV000581284 pathogenic Hereditary cancer-predisposing syndrome 2015-09-30 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),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Center for Human Genetics, Inc RCV000000372 SCV000782009 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000000372 SCV000493060 pathogenic Neurofibromatosis, type 1 2015-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000483061 SCV000566453 pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing The R1362X nonsense variant has been reported previously in association with neurofibromatosis type 1 (Upadhyaya et al., 1997; Evans et al., 2016). The variant has also been confirmed at GeneDx to have occurred de novo in an affected individual. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we consider the variant to be pathogenic.
Invitae RCV000000372 SCV000218850 pathogenic Neurofibromatosis, type 1 2018-09-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1362*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs137854560, ExAC 0.001%). This variant has been reported in several individuals affected with neurofibromatosis type 1 (PMID: 9003501, 10543400, 12112660, 10712197, 24789688). ClinVar contains an entry for this variant (Variation ID: 344). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000372 SCV000020516 pathogenic Neurofibromatosis, type 1 2000-02-01 no assertion criteria provided literature only

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