ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1381C>T (p.Arg461Ter)

dbSNP: rs878853865
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000229618 SCV000284378 pathogenic Neurofibromatosis, type 1 2024-01-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg461*) 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 (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 10862084, 16944272, 23668869). ClinVar contains an entry for this variant (Variation ID: 237514). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255390 SCV000322350 pathogenic not provided 2022-01-28 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23668869, 18438896, 26969325, 26556299, 16479075, 16944272, 15146469, 16835897, 10712197, 10862084, 16941471, 24789688, 23913538, 26659639, 30308447, 29032173, 30098238, 31370276, 32098826, 31776437)
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000229618 SCV000537731 pathogenic Neurofibromatosis, type 1 2015-05-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000492771 SCV000581288 pathogenic Hereditary cancer-predisposing syndrome 2015-08-20 criteria provided, single submitter clinical testing The p.R461* pathogenic mutation (also known as c.1381C>T), located in coding exon 12 of the NF1 gene, results from a C to T substitution at nucleotide position 1381. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been detected in multiple individuals who satisfy NIH diagnostic criteria for NF1 (FahsoldR, et al.Am. J. Hum. Genet. 2000;66(3):790-818;Griffiths S, et al. Fam. Cancer 2007;6(1):21-34;Ko JM, et al.Pediatr.Neurol. 2013;48(6):447-53;JeongSY, et al. J. Korean Med. Sci. 2006;21(1):107-12;MessiaenLM, et al.Hum.Mutat. 2000;15(6):541-55).In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000255390 SCV000885843 pathogenic not provided 2022-03-17 criteria provided, single submitter clinical testing The NF1 c.1381C>T; p.Arg461Ter variant (rs878853865) is reported in the literature in several individuals affected with neurofibromatosis type 1 (Fahsold 2000, Stewart 2008). This variant is absent from general population databases (Exome Variant Server, 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. Based on available information, this variant is considered to be 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 66(3):790-818. Stewart H et al. Congenital disseminated neurofibromatosis type 1: a clinical and molecular case report. Am J Med Genet A. 2008 Jun 1;146A(11):1444-52.
Medical Genetics, University of Parma RCV000229618 SCV001218915 pathogenic Neurofibromatosis, type 1 2019-12-20 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000229618 SCV001479218 pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000255390 SCV002018319 pathogenic not provided 2019-04-03 criteria provided, single submitter clinical testing
3billion RCV000229618 SCV002521365 pathogenic Neurofibromatosis, type 1 2022-05-22 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000237514). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab RCV000229618 SCV002561658 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004547594 SCV004118388 pathogenic NF1-related disorder 2023-05-22 criteria provided, single submitter clinical testing The NF1 c.1381C>T variant is predicted to result in premature protein termination (p.Arg461*). This variant has been reported in multiple individuals with neurofibromatosis (see for examples Fahsold et al. 2000. PubMed ID: 10712197; Giugliano et al. 2019. PubMed ID: 31370276). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in NF1 are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/237514/). This variant is interpreted as pathogenic.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand RCV000229618 SCV004123093 pathogenic Neurofibromatosis, type 1 2023-07-01 criteria provided, single submitter research
Baylor Genetics RCV003475058 SCV004190754 pathogenic Juvenile myelomonocytic leukemia 2023-03-24 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000229618 SCV004698056 pathogenic Neurofibromatosis, type 1 2024-02-08 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4,PS2_MOD
NHS Central & South Genomic Laboratory Hub RCV000229618 SCV005068221 pathogenic Neurofibromatosis, type 1 2024-07-01 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000255390 SCV005199473 pathogenic not provided 2022-07-13 criteria provided, single submitter clinical testing
Laboratory for Genotyping Development, RIKEN RCV003165598 SCV002758175 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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