Submissions for variant NM_001042492.3(NF1):c.910C>T (p.Arg304Ter)

dbSNP: rs786203950

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167474	SCV000218330	pathogenic	Hereditary cancer-predisposing syndrome	2014-12-26	criteria provided, single submitter	clinical testing	The p.R304* pathogenic mutation (also known as c.910C>T), located in coding exon 9 of the NF1 gene, results from a C to T substitution at nucleotide position 910. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been observed in multiple individuals meeting clinical diagnostic criteria for NF1 (De Luca, A et al. Hum Mutat. 2004 Jun;23(6):629; Fahsold, R et al. Am J Hum Genet. 2000 Mar;66(3):790-818; Upadhyaya, M et al. Hum Mutat. 2008 Aug;29(8):E103-11; Ko, JM et al. Pediatr Neurol. 2013 Jun;48(6):447-53). In addition to the clinical data presented in the literature, 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).
Invitae	RCV000468520	SCV000542003	pathogenic	Neurofibromatosis, type 1	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg304*) 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 (rs786203950, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with neurofibromatosis, type 1 (PMID: 10862084, 16786508, 23668869, 23913538). ClinVar contains an entry for this variant (Variation ID: 187722). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NF1 function (PMID: 9463322, 10874316). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000468520	SCV000590893	pathogenic	Neurofibromatosis, type 1	2017-06-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508304	SCV000604459	pathogenic	not specified	2018-08-15	criteria provided, single submitter	clinical testing	The NF1 c.910C>T; p.Arg304Ter variant (rs786203950) has been described in several individuals with neurofibromatosis type 1 (NF1) (see link below, Ko 2013, Upadhyaya 2008). It is reported as pathogenic in ClinVar (Variation ID: 187722) and observed on only 1 allele in the Genome Aggregation Database. 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 pathogenic. References: Link to NF1 LOVD Database for p.Arg304Ter: https://grenada.lumc.nl/LOVD2/mendelian_genes/variants.php?select_db=NF1&action=search_all&search_Variant%2FDNA=c.910C%3ET Ko JM et al. (2013) Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 48(6):447-53. Upadhyaya M et al. (2008) Germline and somatic NF1 gene mutations in plexiform neurofibromas. Hum Mutat. 29(8):E103-11.
GeneDx	RCV000579282	SCV000680718	pathogenic	not provided	2022-08-08	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: 26509978, 27838393, 29695767, 16786508, 25525159, 17295913, 12057013, 12095621, 23668869, 18484666, 23781326, 10712197, 28247034, 29680440, 23913538, 30014477, 30290804, 12112660, 9463322, 10862084, 10874316, 31776437)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000468520	SCV000781883	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000468520	SCV001218910	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000468520	SCV001368730	pathogenic	Neurofibromatosis, type 1	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000579282	SCV001446786	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000468520	SCV001479110	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001294062	SCV001482855	pathogenic	Juvenile myelomonocytic leukemia	2020-02-12	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9463322, 26509978, 10874316, 25525159]
DASA	RCV000468520	SCV002061224	pathogenic	Neurofibromatosis, type 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.910C>T;p.(Arg304*) 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: 187722; PMID: 23668869; 16786508; 23913538; 10862084; 9463322) - PS4. This variant is not present in population databases (rs786203950, 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	RCV000468520	SCV002561612	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498830	SCV002808718	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-03-12	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000468520	SCV003807719	pathogenic	Neurofibromatosis, type 1	2022-06-03	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PP4
PreventionGenetics, part of Exact Sciences	RCV004552933	SCV004118366	pathogenic	NF1-related disorder	2023-02-15	criteria provided, single submitter	clinical testing	The NF1 c.910C>T variant is predicted to result in premature protein termination (p.Arg304*). This variant has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Upadhyaya et al. 2008. PubMed ID: 18484666; Palma Milla et al. 2018. PubMed ID: 30014477). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29527461-C-T). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000579282	SCV004222184	pathogenic	not provided	2016-09-23	criteria provided, single submitter	clinical testing	The NF1 c.910C>T (p.Arg304*) variant causes the premature termination of NF1 protein synthesis. This variant has been reported in the published literature in individuals with neurofibromatosis 1 (NF1) (PMID: 23913538 (2013), 23668869 (2013), 22108604 (2011), 19935827 (2010), 18484666 (2008), 14722917 (2004), 12807981 (2003), 12112660 (2002), 10862084 (2000), 10712197 (2000)). Published functional studies show that this variant results in skipping of exon 7 and produces an aberrant transcript (PMID: 17295913 (2007), 26509978 (2015), 9463322 (1998)). The frequency of this variant in the general population, 0.000004 (1/251414 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Coyote Medical Laboratory (Beijing), Coyote	RCV000468520	SCV001441284	pathogenic	Neurofibromatosis, type 1	2017-10-29	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000579282	SCV001959590	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000579282	SCV001966481	pathogenic	not provided		no assertion criteria provided	clinical testing