Submissions for variant NM_001042492.3(NF1):c.1318C>T (p.Arg440Ter)

gnomAD frequency: 0.00001  dbSNP: rs778405030

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213237	SCV000274305	pathogenic	Hereditary cancer-predisposing syndrome	2015-03-04	criteria provided, single submitter	clinical testing	​<span style="background-color:initial">The p.R440* pathogenic mutation (also known as c.1318C>T), located in coding exon 12 of the NF1 gene, results from a C to T substitution at nucleotide position 1318. This changes the amino acid from an arginine to a stop codon within exon 12. This mutation has been reported in several individuals diagnosed with NF1 (Heim et al. Hum Mol Genet. 1995. 4(6):975-981; Fahsold et al. Am J Hum Genet. 2000. 66:790-818; Kluwe, et al. Hum Mutat. 2003 Nov;22(5):420). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, p.R440* 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).
Invitae	RCV000225855	SCV000284377	pathogenic	Neurofibromatosis, type 1	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg440*) 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 (rs778405030, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 7655472, 10543400, 10712197, 10862084, 16835897, 23668869, 24922668). ClinVar contains an entry for this variant (Variation ID: 230673). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000519956	SCV000616807	pathogenic	not provided	2022-02-16	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; This variant is associated with the following publications: (PMID: 7655472, 11940628, 16835897, 31212687, 31717729, 25525159, 10712197, 26744134, 28454108, 9452037, 15060124, 10862084, 30014477, 10336779, 23668869, 14517963, 24232412, 25925892, 10543400, 30713041, 30290804, 31370276, 30530636, 31730495, 31776437, 29625052)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000225855	SCV000781902	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762984	SCV000893429	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-03-09	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000225855	SCV001218914	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000225855	SCV001479031	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814122	SCV001755241	pathogenic	Abnormality of the skin	2021-07-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000225855	SCV002030196	pathogenic	Neurofibromatosis, type 1	2021-02-09	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000225855	SCV002561656	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000519956	SCV002771575	pathogenic	not provided	2021-07-14	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 at least one individual with clinical features associated with this gene.
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003315237	SCV004012922	pathogenic	Neurofibrmatosis type 1	2021-10-07	criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000225855	SCV004014626	pathogenic	Neurofibromatosis, type 1	2023-07-19	criteria provided, single submitter	clinical testing
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV000225855	SCV004037360	pathogenic	Neurofibromatosis, type 1	2020-04-10	criteria provided, single submitter	clinical testing	The c. 1318C>T variant is a heterozygous single base pair substitution at nucleotide 1318 in exon 12 of 58 of the NF1 gene, resulting in a premature translational stop signal at amino acid 440 of 2840 (p.Arg440Ter), and is expected to cause nonsense mediated mRNA decay. This variant is observed in the Genome Aggregation Database (gnomAD) at a very low frequency (2/251,412), indicating it is not a common benign variant in the populations represented in this database. This variant has been observed in the heterozygous state in multiple individuals with clinical features of Neurofibromatosis, type 1 (PMIDs: 24232412, 30530636, 7655472, 23668869, 16835897, 10862084, 10543400, 10712197, and 24922668). This variant has been reported in ClinVar as Pathogenic by multiple submitters (Variation ID: 230673; Last accessed: 3/25/2020).
Baylor Genetics	RCV003469010	SCV004198376	pathogenic	Juvenile myelomonocytic leukemia	2023-08-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000519956	SCV004222152	pathogenic	not provided	2021-07-14	criteria provided, single submitter	clinical testing	This variant causes the premature termination of NF1 protein synthesis. In addition, this variant has been reported as pathogenic in individuals with Neurofibromatosis type 1 in the published literature (PMIDs: 7655472 (1995), 15060124 (2004), and 23668869 (2013)). Based on the available information, this variant is classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000225855	SCV004809487	pathogenic	Neurofibromatosis, type 1	2024-04-04	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000519956	SCV001954158	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000519956	SCV001973749	pathogenic	not provided		no assertion criteria provided	clinical testing