Submissions for variant NM_001042492.3(NF1):c.1246C>T (p.Arg416Ter)

dbSNP: rs764079291

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467266	SCV000542209	pathogenic	Neurofibromatosis, type 1	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg416*) 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 (rs764079291, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 10543400, 10712197, 15060124, 23668869, 25325900). ClinVar contains an entry for this variant (Variation ID: 404597). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000484297	SCV000568600	pathogenic	not provided	2022-04-27	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: 25541118, 29922827, 25525159, 22155606, 29185159, 23244495, 25325900, 15060124, 23668869, 26969325, 29082380, 10712197, 29290338, 10543400, 24789688, 31370276, 30530636, 30290804, 29914388, 29489754, 27535533)
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000467266	SCV000746691	pathogenic	Neurofibromatosis, type 1	2017-12-18	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000467266	SCV000781899	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000484297	SCV000884242	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing	The NF1 c.1246C>T; p.Arg416Ter variant (rs764079291) has been reported in several unrelated individuals affected with neurofibromatosis type 1 (Fahsold 2000, Ko 2013, Maruoka 2014, Osborn 1999, Xu 2014). It is also reported in ClinVar (Variation ID: 404597). This variant is only observed on one allele in the 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 Mar;66(3):790-818. PMID: 10712197. Ko JM et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 2013 Jun;48(6):447-53. PMID: 23668869 Maruoka R et al. The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study. Genet Test Mol Biomarkers. 2014 Nov;18(11):722-35. PMID: 25325900. Osborn MJ et al. Evaluation of the protein truncation test and mutation detection in the NF1 gene: mutational analysis of 15 known and 40 unknown mutations. Hum Genet. 1999 Oct;105(4):327-32. PubMed: 10543400. Xu W et al. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. Int J Mol Med. 2014 Jul;34(1):53-60. PMID: 24789688.
CeGaT Center for Human Genetics Tuebingen	RCV000484297	SCV001247183	pathogenic	not provided	2018-09-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000467266	SCV001429440	pathogenic	Neurofibromatosis, type 1	2018-08-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000467266	SCV001479121	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000467266	SCV001519440	pathogenic	Neurofibromatosis, type 1	2021-03-11	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.1246C>T (p.Arg416X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250118 control chromosomes. c.1246C>T has been widely reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (example, Osborne_1999, Fahsold_2000, Sabbagh_2013). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000467266	SCV002073161	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing	The stop gained p.R416* in NF1 (NM_000267.3) has been reported tpreviously in multiple affected individuals (Maruoka 2014; Hutter 2016). It has been submitted to ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000467266	SCV002512198	pathogenic	Neurofibromatosis, type 1	2021-06-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4, PM2 moderate
Genome-Nilou Lab	RCV000467266	SCV002561645	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002393083	SCV002669878	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-06-28	criteria provided, single submitter	clinical testing	The p.R416* pathogenic mutation (also known as c.1246C>T), located in coding exon 11 of the NF1 gene, results from a C to T substitution at nucleotide position 1246. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been identified in numerous individuals with clinical diagnoses of neurofibromatosis type 1 (NF1) (Osborn MJ et al. Hum. Genet. 1999 Oct;105:327-32; Ko JM et al. Pediatr. Neurol. 2013 Jun;48:447-53; Maruoka R et al. Genet. Test Mol. Biomarkers. 2014 Nov;18:722-35; Hutter S et al. Hum. Genet. 2016 May;135:469-75; Mao B et al. BMC Med Genet, 2018 06;19:101; Melloni G et al. Cancers (Basel), 2019 11;11:; Frayling IM et al. J Med Genet, 2019 04;56:209-219; Giugliano T et al. Genes (Basel), 2019 07;10:). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002502604	SCV002811849	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-03-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV003483615	SCV004232442	pathogenic	Neurofibromatosis-Noonan syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PS2;PVS1
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000484297	SCV001952839	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000484297	SCV001966881	pathogenic	not provided		no assertion criteria provided	clinical testing