Submissions for variant NM_000267.3(NF1):c.6709C>T (p.Arg2237Ter) (rs876658541)

Total submissions: 8

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	2019-11-29	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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 12552569, 23913538, 16479075, 10862084, 26962827). This variant is also known as R2258X in the literature. ClinVar contains an entry for this variant (Variation ID: 230389). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000578739	SCV000680725	pathogenic	not provided	2018-12-20	criteria provided, single submitter	clinical testing	The R2237X nonsense variant in the NF1 gene has been reported previously in association with neurofibromatosis type 1 (Fahsold et al., 2000; Jeong et al., 2006). It has also been observed apparently de novo in at least one patient previously tested at GeneDx. The R2237X variant is not observed in large population cohorts (Lek et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
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 pseudoarthrosis	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