ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7486C>T (p.Arg2496Ter) (rs866445127)

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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 RCV000505900 SCV000604508 pathogenic not specified 2016-11-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000218957 SCV000274026 pathogenic Hereditary cancer-predisposing syndrome 2015-02-18 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)
Center for Human Genetics, Inc RCV000457951 SCV000782105 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000579098 SCV000680726 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing The R2496X nonsense variant in the NF1 gene has been reported previously in association with NF1 (Park et al., 1998; Fahsold et al., 2000; Messiaen et al., 2000; Cali 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 R2496X variant is not observed in large population cohorts (Lek et al., 2016). Based on currently available evidence, we consider R2496X to be pathogenic.
GenomeConnect, ClinGen RCV000457951 SCV000986762 not provided Neurofibromatosis, type 1 no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 02/09/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000457951 SCV000917894 pathogenic Neurofibromatosis, type 1 2018-05-25 criteria provided, single submitter clinical testing Variant summary: NF1 c.7486C>T (p.Arg2496X) results in a premature termination codon, predicted to cause a truncation of the encoded protein (12%) or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 121268 control chromosomes. The c.7486C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1, both in sporadic and familial cases. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000457951 SCV000541947 pathogenic Neurofibromatosis, type 1 2018-11-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2496*) 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 in individuals with neurofibromatosis type 1 (PMID: 25324867, 7981679, 22965773, 10712197, 16835897). This variant is also known as p.Arg2517* in the literature. ClinVar contains an entry for this variant (Variation ID: 230467). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center RCV000788089 SCV000927087 pathogenic Neurofibromas 2018-12-13 criteria provided, single submitter clinical testing

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