Submissions for variant NM_001042492.3(NF1):c.6772C>T (p.Arg2258Ter)

dbSNP: rs876658541

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223234	SCV000273924	pathogenic	Hereditary cancer-predisposing syndrome	2015-01-08	criteria provided, single submitter	clinical testing	​Thep.R2258*pathogenic mutation (also known as c.6772C>T, p.R2237X, and c.6709C>T)<span style="font-size:12.7272720336914px">located in coding exon 45 of theNF1<span style="font-size:12.7272720336914px">gene, results from a C to T substitution at nucleotide position 6772. This changes the amino acid from an arginine to a stop codon within coding exon 45. This alteration was first described in three unrelated individuals who all met NIH diagnostic criteria forneurofibromatosis type 1 (NF1) (Fahsold R et al.Am J Hum Genet.2000;66(3):790-818). This alteration is a recurring mutation due to being located in a CpG dinucleotide. 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	RCV000461033	SCV000541996	pathogenic	Neurofibromatosis, type 1	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2237*) 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, 10862084, 12552569, 16479075, 23913538, 26962827). This variant is also known as R2258X. ClinVar contains an entry for this variant (Variation ID: 230389). 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.
GeneDx	RCV000578739	SCV000680725	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: 26962827, 10712197, 16479075, 25525159, 12112660, 27498913, 27617404, 12552569, 23913538, 10862084, 34308366, 31730495, 31717729, 31533797, 31370276, 32283115, 31776437)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000461033	SCV000782084	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000461033	SCV001140392	pathogenic	Neurofibromatosis, type 1	2019-05-28	criteria provided, single submitter	clinical testing
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009581	SCV001169682	pathogenic	Neurofibromatosis, type 1; Tibial pseudarthrosis	2018-11-10	criteria provided, single submitter	research
Medical Genetics, University of Parma	RCV000461033	SCV001218926	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000578739	SCV001446559	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000461033	SCV001478132	pathogenic	Neurofibromatosis, type 1	2020-12-15	criteria provided, single submitter	research
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000461033	SCV001479220	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000578739	SCV001747871	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing
3billion	RCV000461033	SCV002521550	pathogenic	Neurofibromatosis, type 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000230389 / PMID: 10712197). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000461033	SCV002560209	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000461033	SCV002769401	pathogenic	Neurofibromatosis, type 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene and is associated with NF1-related disorders. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. A child can be more or less severly affected than a heterozygote parent (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - Variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple patients with NF1, including some cases with confirmed de novo inheritance (ClinVar, PMID: 10712197, 31776437). (SP) 1208 - Inheritance information for this variant is not currently available. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Suma Genomics	RCV000461033	SCV004037088	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000461033	SCV004809614	pathogenic	Neurofibromatosis, type 1	2024-04-04	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000578739	SCV001958068	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000578739	SCV001964686	pathogenic	not provided		no assertion criteria provided	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000461033	SCV002555588	pathogenic	Neurofibromatosis, type 1		no assertion criteria provided	research
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000461033	SCV003840142	pathogenic	Neurofibromatosis, type 1		no assertion criteria provided	research