Submissions for variant NM_000267.3(NF1):c.7846C>T (p.Arg2616Ter) (rs786201367)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163482	SCV000214039	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-04	criteria provided, single submitter	clinical testing	The p.R2637* pathogenic mutation (also known as c.7909C>T), located in coding exon 54 of the NF1 gene, results from a C to T substitution at nucleotide position 7909. This changes the amino acid from an arginine to a stop codon within coding exon 54. This pathogenic mutation has been described in an individual who presented with classic cutaneous involvement and plexiform neurofibromas (Upadhyaya M et al. J. Med. Genet. 1995; 32:706-10). In addition, this alteration was also found in an affected patient presenting with Cafe-au-Lait spots, axillary freckling, nodular neurofibromas, lisch nodules and scoliosis (De Luca A et al. Hum. Mutat. 2004; 23:629). 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). This mutation is also known as p.R2616* and c.7846C>T in the literature.
UCLA Clinical Genomics Center, UCLA	RCV000196216	SCV000255422	likely pathogenic	Neurofibromatosis, type 1	2013-04-30	criteria provided, single submitter	clinical testing
Invitae	RCV000196216	SCV000541988	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal at codon 2616 (p.Arg2616*) of the NF1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with neurofibromatosis type 1 (PMID: 8544190, 15146469, 25074460, 10712197, 25326637, 27838393). ClinVar contains an entry for this variant (Variation ID: 184261). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000515434	SCV000611289	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2017-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000599610	SCV000709955	pathogenic	not provided	2018-09-14	criteria provided, single submitter	clinical testing	The R2616X variant in the NF1 gene has been reported in multiple individuals with Neurofibromatosis type 1 syndrome (Upadhyaya et al., 1995; Fahsold et al., 2000; Pasmant et al., 2015, Cali et al., 2016). This substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The R2616X variant is not observed in large population cohorts (Lek et al., 2016). Based on currently available evidence, we consider R2616X to be a pathogenic variant, consistent with the diagnosis of neurofibromatosis type 1 in this individual.
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000196216	SCV000782115	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000196216	SCV000915756	pathogenic	Neurofibromatosis, type 1	2018-09-06	criteria provided, single submitter	clinical testing	The NF1 c.7846C>T (p.Arg2616Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg2616Ter variant has been reported in at least nine studies and is found in at least 25 probands in a heterozygous state (Upadhyaya et al. 1995; Osborn et al. 1999; Fahsold et al. 2000; Wang et al. 2003; De Luca et al. 2004; Shirinzi et al. 2006; Stevenson et al. 2006; Messiaen and Wimmer 2008; Vuralli et al. 2016). Two probands were related and had clinical features of NF1 and neurofibromatosis-Noonan syndrome. The p.Arg2616Ter variant was absent from 152 controls (De Luca et al. 2004; Shirinzi et al. 2006) and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or Genome Aggregation Database. Due to the potential impact of stop-gained variants and the evidence in the literature, the p.Arg2616Ter variant is classified as pathogenic for NF1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009586	SCV001169687	pathogenic	Neurofibromatosis, type 1; Tibial pseudoarthrosis	2018-11-10	criteria provided, single submitter	research
Medical Genetics, University of Parma	RCV000196216	SCV001218931	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000196216	SCV000692369	pathogenic	Neurofibromatosis, type 1	2015-08-28	no assertion criteria provided	clinical testing