Submissions for variant NM_001042492.3(NF1):c.7348C>T (p.Arg2450Ter)

dbSNP: rs786202457

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165277	SCV000215994	pathogenic	Hereditary cancer-predisposing syndrome	2014-08-07	criteria provided, single submitter	clinical testing	The p.R2450* pathogenic mutation (also known as c.7348C>T) located in coding exon 50 of the NF1 gene, results from a C to T substitution at nucleotide position 7348. This changes the amino acid from an arginine to a stop codon within coding exon 50. 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).
GeneDx	RCV000414562	SCV000491219	pathogenic	not provided	2022-11-02	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: 16835897, 18484666, 16944272, 14722917, 34427956, 25525159, 22108604, 15060124, 16941471, 10336779, 22155606, 28422438, 10862084, 25074460, 31370276, 10712197, 31730495, 32642735, 30290804, 30877234, 29625052, 27535533, 31776437, 35456261)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414830	SCV000492732	pathogenic	Lisch nodules; Subcutaneous neurofibroma	2015-09-28	criteria provided, single submitter	clinical testing
Invitae	RCV000532076	SCV000628770	pathogenic	Neurofibromatosis, type 1	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2429*) 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 neurofibromatosis type 1 (PMID: 10712197, 16835897, 16944272, 25074460). ClinVar contains an entry for this variant (Variation ID: 185789). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999932	SCV000884234	pathogenic	not specified	2018-09-14	criteria provided, single submitter	clinical testing	The NF1 c.7348C>T; p.Arg2450Ter variant (rs786202457) is reported in the literature in multiple individuals affected with neurofibromatosis type I (Fahsold 2000, Griffiths 2007, Lee 2006). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 185789), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The 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, the p.Arg2450Ter 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; 66(3):790-818. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Lee MJ et al. Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Hum Mutat. 2006 Aug;27(8):832.
Medical Genetics, University of Parma	RCV000532076	SCV001218930	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000414562	SCV001446869	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000414562	SCV001470149	pathogenic	not provided	2020-03-02	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Athena Diagnostics	RCV000414562	SCV001476714	pathogenic	not provided	2020-03-02	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000532076	SCV001479022	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
DASA	RCV000532076	SCV002061225	pathogenic	Neurofibromatosis, type 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.7285C>T;p.(Arg2429*) variant creates a premature translational stop signal in the NF1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 185789; PMID: 10712197; 16944272; 16835897; 25074460) - PS4. This variant is not present in population databases (rs786202457, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
Genome-Nilou Lab	RCV000532076	SCV002560570	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004552904	SCV004120471	pathogenic	NF1-related disorder	2023-03-13	criteria provided, single submitter	clinical testing	The NF1 c.7348C>T variant is predicted to result in premature protein termination (p.Arg2450*). This variant is alternatively referred to as c.7285C>T (p.Arg2429*) using the primary transcript NM_000267. This variant has been reported in multiple individuals with neurofibromatosis type I (Fahsold et al. 2000. PubMed ID: 10712197; Lee et al. 2006. PubMed ID: 16835897; Griffiths et al. 2007. PubMed ID: 16944272). At PreventionGenetics, we previously identified this variant in other affected patients. To our knowledge, this variant has not been reported in in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185789/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003468738	SCV004190698	pathogenic	Juvenile myelomonocytic leukemia	2023-06-02	criteria provided, single submitter	clinical testing
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332130	SCV004040620	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research