Submissions for variant NM_001042492.3(NF1):c.4084C>T (p.Arg1362Ter)

dbSNP: rs137854560

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000000372	SCV000218850	pathogenic	Neurofibromatosis, type 1	2024-01-05	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. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is present in population databases (rs137854560, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9003501, 10543400, 10712197, 12112660, 24789688; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 344). For these reasons, this variant has been classified as Pathogenic.
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	2022-02-25	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; Identified in patients with clinically diagnosed neurofibromatosis type 1 in published literature (Fahsold 2000, Evans 2016, Tsipi 2018); This variant is associated with the following publications: (PMID: 28852190, 28356599, 27236105, 10712197, 9003501, 25525159, 25541118, 27322474, 23668869, 14517963, 23913538, 24789688, 12112660, 10543400, 30308447, 29625052, 31776437, 31717729, 33674644)
Ambry Genetics	RCV000492495	SCV000581284	pathogenic	Hereditary cancer-predisposing syndrome	2015-09-30	criteria provided, single submitter	clinical testing	The p.R1362* pathogenic mutation (also known as c.4084C>T), located in coding exon 30 of the NF1 gene, results from a C to T substitution at nucleotide position 4084. This changes the amino acid from an arginine to a stop codon within coding exon 30. This mutation has beendetectedin multipleindividuals satisfying NIH diagnostic criteria for NF1 (FahsoldRet al.Am. J. Hum. Genet. 2000; 66(3):790-818;Ko JMet al.Pediatr.Neurol. 2013; 48(6):447-53;KluweLet al.Hum.Mutat. 2003; 22(5):420).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).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000000372	SCV000782009	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
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.
Medical Genetics, University of Parma	RCV000000372	SCV001218922	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000000372	SCV001479217	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000000372	SCV001571435	pathogenic	Neurofibromatosis, type 1	2021-02-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000483061	SCV002018317	pathogenic	not provided	2023-07-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000000372	SCV002560020	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000000372	SCV002581653	pathogenic	Neurofibromatosis, type 1	2022-07-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000483061	SCV002771578	pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene.
Fulgent Genetics, Fulgent Genetics	RCV002504730	SCV002812522	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-01-19	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000000372	SCV004030446	pathogenic	Neurofibromatosis, type 1	2023-08-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000483061	SCV004224639	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
OMIM	RCV000000372	SCV000020516	pathogenic	Neurofibromatosis, type 1	2000-02-01	no assertion criteria provided	literature only