Submissions for variant NM_001042492.3(NF1):c.5305C>T (p.Arg1769Ter)

dbSNP: rs876657714

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220916	SCV000271425	pathogenic	Neurofibromatosis, type 1	2016-01-12	criteria provided, single submitter	clinical testing	The p.Arg1769X variant in NF1 (NM_001042492.2) has been identified in 12 individ uals with NF1 and segregated with disease in 2 affected relatives (reported as p .Arg1748X on NM_000267.3 in the following: Valero 1994, Peters 1999, Fashold 200 0, Girodon-Boulandet 2000, Origone 2002, Raponi 2009, Sabbagh 2013). It was abse nt from large population studies. This nonsense variant leads to a premature ter mination codon at position 1769, which is predicted to lead to a truncated or ab sent protein. Heterozygous loss of function of the NF1 gene is an established d isease mechanism in NF1. In summary, this variant meets our criteria to be class ified as pathogenic for NF1 in an autosomal dominant manner based upon multiple affected probands, absence from controls, and predicted impact on the protein.
Invitae	RCV000220916	SCV000542107	pathogenic	Neurofibromatosis, type 1	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1748*) 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 sporadic or familial neurofibromatosis type 1 (PMID: 8069310, 12746402, 12807981, 16944272, 19221814). ClinVar contains an entry for this variant (Variation ID: 228381). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000483267	SCV000568611	pathogenic	not provided	2022-02-02	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: 27862945, 22155606, 15627836, 10712197, 31730495, 31717729, 32860008, 25525159, 12807981, 12112660, 19221814, 18546366, 20015894, 20605257, 23244495, 21031597, 10980545, 16944272, 12746402, 19292874, 8069310, 27838393, 28955729, 10090487, 30530636, 33372952, 31776437, 34694046, 33332384)
Ambry Genetics	RCV002311062	SCV000581350	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-07-18	criteria provided, single submitter	clinical testing	The p.R1748* pathogenic mutation (also known as c.5242C>T), located in coding exon 37 of the NF1 gene, results from a C to T substitution at nucleotide position 5242. This changes the amino acid from an arginine to a stop codon within coding exon 37. This mutation has been seen in several individuals who met NIH consensus or diagnostic criteria for neurofibromatosis type 1 (NF1) (Valero MC et al. Hum. Mol. Genet. 1994 Apr;3(4):639-41; Fahsold R et al. Am. J. Hum. Genet. 2000 Mar;66(3):790-818; Trovó-Marqui AB et al. Ophthalmic Res. 2004 Sept;36:349-52; Sites ER et al. Am. J. Med. Genet. A. 2017 Mar;173:647-653). 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000220916	SCV000782048	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000483267	SCV000885842	pathogenic	not provided	2017-10-12	criteria provided, single submitter	clinical testing	The NF1 c.5305C>T, p.Arg1769Ter variant (rs876657714) has been reported in multiple patients diagnosed with neurofibromatosis type I (Fahsold 2000, Girodon-Boulandet 2000, Peters 1999). It is listed as pathogenic in ClinVar (Variation ID: 228381), and not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the p.Arg1769Ter 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; 66(3):790-818. Girodon-Boulandet E et al. NF1 gene analysis focused on CpG-rich exons in a cohort of 93 patients with neurofibromatosis type 1. Hum Mutat. 2000; 16(3):274-5. Peters H et al. Mutation screening of neurofibromatosis type 1 (NF1) exons 28 and 29 with single strand conformation polymorphism (SSCP): five novel mutations, one recurrent transition and two polymorphisms in a panel of 118 unrelated NF1 patients. Hum Mutat. 1999; 13(3):258.
Centogene AG - the Rare Disease Company	RCV000220916	SCV001426647	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000220916	SCV001440185	pathogenic	Neurofibromatosis, type 1	2019-01-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000220916	SCV001479015	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000483267	SCV001761998	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000483267	SCV002522529	pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
Genome-Nilou Lab	RCV000220916	SCV002560113	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000483267	SCV002563400	pathogenic	not provided	2022-05-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000220916	SCV002581142	pathogenic	Neurofibromatosis, type 1	2022-07-27	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000483267	SCV002771576	pathogenic	not provided	2022-05-05	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with NF1.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257531	SCV001434357	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332144	SCV004040619	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research