Submissions for variant NM_000267.3(NF1):c.6791dup (p.Tyr2264Ter)

dbSNP: rs876657715

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213933	SCV000271426	pathogenic	Neurofibromatosis, type 1	2016-03-28	criteria provided, single submitter	clinical testing	The p.Tyr2285X variant in NF1 has been reported in >10 individuals with Neurofib romatosis I (NF1) (Upadhyaya 1996, Leiden Open Variation Database), 3 of which w ere apparently de novo. It was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This nonsen se variant leads to a premature termination codon at position 2285, which is pre dicted to lead to a truncated or absent protein. Heterozygous loss-of-function o f the NF1 gene is an established disease mechanism in NF1. In summary, this vari ant meets our criteria to be classified as pathogenic for NF1 in an autosomal do minant manner.
GeneDx	RCV000486063	SCV000568612	pathogenic	not provided	2022-05-06	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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31370276, 10494088, 27322474, 27838393, 8837715, 15146469, 29566708, 29618358, 24232412, 16941471, 29914388, 30308447, 31533797, 32107864, 25325900, 31776437)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000213933	SCV000816867	pathogenic	Neurofibromatosis, type 1	2024-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2264*) 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 individuals with neurofibromatosis type 1 (PMID: 8837715, 16941471, 17311297, 23913538, 24232412, 25325900, 27838393). This variant is also known as p.Tyr2285*. ClinVar contains an entry for this variant (Variation ID: 228382). For these reasons, this variant has been classified as Pathogenic.
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009583	SCV001169684	pathogenic	Neurofibromatosis, type 1; Tibial pseudarthrosis	2018-11-10	criteria provided, single submitter	research
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000213933	SCV001479139	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000213933	SCV001934323	pathogenic	Neurofibromatosis, type 1	2020-11-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000486063	SCV002048243	pathogenic	not provided	2021-01-08	criteria provided, single submitter	clinical testing	The NF1 c.6854dupA;p.Tyr2285Ter variant (also known as c.6791dupA;p.Tyr2264Ter) is published in the medical literature in several individuals with a clinical diagnosis of neurofibromatosis type 1 (De Luca 2004, Maruoka 2014, Upadhyaya 1996). The variant is listed in the ClinVar database (Variation ID: 228382), but not in the dbSNP variant database or in the general population-based databases (Exome Variant Server, Genome Aggregation Database). This variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to non-sense mediated decay. Considering available information, this variant is classified as pathogenic. References: De Luca A et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum Mutat. 2004 Jun;23(6):629. Maruoka R et al. The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study. Genet Test Mol Biomarkers. 2014 Nov;18(11):722-35. Upadhyaya M et al. Characterization of six mutations in exon 37 of neurofibromatosis type 1 gene. Am J Med Genet. 1996 Jul 26;67(4):421-3.
Genome-Nilou Lab	RCV000213933	SCV002560215	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000213933	SCV002580391	pathogenic	Neurofibromatosis, type 1	2021-09-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002363071	SCV002663774	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-08-16	criteria provided, single submitter	clinical testing	The c.6791dupA pathogenic mutation, located in coding exon 45 of the NF1 gene, results from a duplication of A at nucleotide position 6791, causing a translational frameshift with a predicted alternate stop codon (p.Y2264*). This alteration has been reported in multiple unrelated individuals with neurofibromatosis type 1 (Upadhyaya M et al. Am J Med Genet, 1996 Jul;67:421-3; Pros E et al. Hum Mutat, 2006 Nov;27:1104-14; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Mao B et al. BMC Med Genet, 2018 06;19:101; Melloni G et al. Cancers (Basel), 2019 Nov;11; Zhu G et al. Orphanet J Rare Dis, 2019 Sep;14:221; Giugliano T et al. Genes (Basel), 2019 Jul;10:). 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000486063	SCV005196979	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796109	SCV005415830	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Supporting+PP4