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

dbSNP: rs878853865

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	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
Laboratory for Genotyping Development, RIKEN	RCV003165598	SCV002758175	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research