Submissions for variant NM_000267.3(NF1):c.2033dup (p.Ile679fs) (rs587781807)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130078	SCV000184905	pathogenic	Hereditary cancer-predisposing syndrome	2015-03-11	criteria provided, single submitter	clinical testing	The c.2033dupC pathogenic mutation (also known as 2027insC and 2033insC), located in coding exon 18 of the NF1 gene, results from a duplication of C at nucleotide position 2033, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in mutliple NF1 patients (Heim RA et al. Hum. Mol. Genet. 1995; 4:975-81; Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818). In addition to the clinical data presented in the literature, since frameshifts 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	RCV000204850	SCV000259531	pathogenic	Neurofibromatosis, type 1	2019-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile679Aspfs*21) in the NF1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs780157990, ExAC 0.02%). This variant has been reported in the literature in individuals affected with neurofibromatosis type 1 (PMID: 7655472, 17311297, 23656349, 18546366, 23668869, 21354044). It is also known as 2027insC and c.2033_2034insC in the literature. ClinVar contains an entry for this variant (Variation ID: 141513). 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	RCV000265986	SCV000329838	pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing	The c.2033dupC variant in the NF1 gene has been frequently reported in association with NF1 (Heim et al., 1995; Valero et al., 2011) and in one patient with NF1 and juvenile myelomonocytic leukemia (JMML) (van Minkelen et al., 2014). This duplication causes a frameshift starting with codon Isoleucine 679, changes this amino acid to an Aspartic Acid residue and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Ile679AspfsX21. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense mediated mRNA decay. The c.2033dupC variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000204850	SCV000781935	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009578	SCV001169679	pathogenic	Neurofibromatosis, type 1; Tibial pseudoarthrosis	2018-11-10	criteria provided, single submitter	research
Medical Genetics, University of Parma	RCV000204850	SCV001218918	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001287403	SCV001474094	pathogenic	none provided	2020-03-19	criteria provided, single submitter	clinical testing	The NF1 c.2033dupC; p.Ile679AspfsTer21 variant (rs587781807), is reported in the literature in multiple individuals affected with neurofibromatosis type I (NF1; Duat 2015, Ko 2013, LaDuca 2017, Pros 2008, Valero 2011, van Minkelen 2014, Wimmer 2007). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 141513), and is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Duat Rodríguez A et al. Phenotypic and genetic features in neurofibromatosis type 1 in children. An Pediatr (Barc). 2015 Sep;83(3):173-82. Ko JM et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 2013 Jun;48(6):447-53. LaDuca H et al. Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. PLoS One. 2017 Feb 2;12(2):e0170843. Pros E et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008 Sep;29(9):E173-93. Valero MC et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011 Mar;13(2):113-22. van Minkelen R et al. A clinical and genetic overview of 18?years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet. 2014 Apr;85(4):318-27. Wimmer K et al. Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption. Hum Mutat. 2007 Jun;28(6):599-612.