Submissions for variant NM_001042492.3(NF1):c.2446C>T (p.Arg816Ter)

dbSNP: rs886041347

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000376782	SCV000329837	pathogenic	not provided	2020-12-16	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; Observed in multiple patients with Neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature, including both apparent and confirmed de novo observations (Maynard 1997, Fahsold 2000, Jeong 2006, Ko 2013, Cali 2016, Pemov 2017, Cannon 2018, Tsipi 2018); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 10712197, 30192422, 15146469, 32486389, 32408052, 9150739, 23668869, 9475595, 27838393, 16479075, 27498913, 25403449, 30014477, 19142971, 26969325, 18484666, 16773574, 29146900, 31730495, 29415745, 28068329, 30308447, 31766501, 31776437)
Ambry Genetics	RCV002311233	SCV000581352	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-01-27	criteria provided, single submitter	clinical testing	The p.R816* variant (also known as c.2446C>T), located in coding exon 21 of the NF1 gene, results from a C to T substitution at nucleotide position 2446. This changes the amino acid from an arginine to a stop codon within coding exon 21. This mutation has been reported multiple times in individuals with clinical features of neurofibromatosis type 1 (Maynard et al. Hum. Genet. 1997; 99:674-76; Bahuau et al. Am J Med Genet. 1998;75(3):265-72; Fahsold et al. Am. J. Hum. Genet. 2000; 66(3):790-818; Jeong et al. J. Korean Med. Sci. 2006;21(1):107-12; Bottillo et al. J. Pathol. 2009; 217(5):693-701; Stenman et al. Endocr. Pathol. 2015; 26(1):9-14; Kang E et al. J Hum Genet, 2020 Jan;65:79-89; N Abdel-Aziz N et al. Mol Genet Genomic Med, 2021 12;9:e1631). This mutation also segregated with disease in ten individuals from one family with neurofibromatosis (Bahuau et al. Am J Med Genet. 1998. 23;75(3):265-72). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Medical Genetics, University of Parma	RCV000497042	SCV000588746	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Invitae	RCV000497042	SCV000628443	pathogenic	Neurofibromatosis, type 1	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg816*) 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 NF1-related conditions (PMID: 9150739, 9475595, 10712197, 15146469, 18484666, 19142971, 23668869, 25403449). ClinVar contains an entry for this variant (Variation ID: 280055). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626642	SCV000747344	pathogenic	Cafe au lait spots, multiple; Axillary freckling; Large cafe-au-lait macules with irregular margins; Lisch nodules; Delayed fine motor development; Inguinal freckling	2017-01-01	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000497042	SCV000781952	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762986	SCV000893431	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000376782	SCV000927362	pathogenic	not provided	2017-07-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000376782	SCV001247188	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000497042	SCV001479119	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000497042	SCV002061403	pathogenic	Neurofibromatosis, type 1	2021-04-05	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
Genome-Nilou Lab	RCV000497042	SCV002561770	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000497042	SCV004027791	pathogenic	Neurofibromatosis, type 1	2023-05-02	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3_MOD,PS4_MOD,PM2_SUP
Baylor Genetics	RCV003469215	SCV004190764	pathogenic	Juvenile myelomonocytic leukemia	2023-02-21	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000497042	SCV001190818	pathogenic	Neurofibromatosis, type 1	2020-02-05	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000376782	SCV001739596	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000376782	SCV001975048	pathogenic	not provided		no assertion criteria provided	clinical testing