Submissions for variant NM_000267.3(NF1):c.4537C>T (p.Arg1513Ter) (rs760703505)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206013	SCV000260477	pathogenic	Neurofibromatosis, type 1	2019-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1513*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This is a recurrent variant that has been reported in many unrelated individuals affected with neurofibromatosis type 1 (PMID: 9180088, 10712197, 16479075, 21354044, 23668869, 26969325). ClinVar contains an entry for this variant (Variation ID: 220152). 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	RCV000255589	SCV000322356	pathogenic	not provided	2018-10-24	criteria provided, single submitter	clinical testing	The R1513X variant in the NF1 gene has been reported previously in association with neurofibromatosis, type 1 (Kluwe et al., 2003; Mattocks et al., 2004; Jeong et al., 2006). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1513X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000415187	SCV000492997	likely pathogenic	Neurofibromatosis type 6; Thoracic scoliosis; Subcutaneous neurofibromas	2014-09-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492716	SCV000581282	pathogenic	Hereditary cancer-predisposing syndrome	2016-01-18	criteria provided, single submitter	clinical testing	The p.R1534* pathogenic mutation (also known as c.4600C>T), located in coding exon 35 of the NF1 gene, results from a C to T substitution at nucleotide position 4600. This changes the amino acid from an arginine to a stop codon within coding exon 35. This mutation has been observed in multiple neurofibromatosis type 1 (NF1) families,<span style="background-color:initial">including one family in which the mutation segregated with NF1 in a proband diagnosed with juvenile myelomonocytic leukemia at 14 months and his affected mother (<span style="background-color:initial">Ko JMet al. Pediatr. Neurol. 2013 Jun;48(6):447-53,Side Let al. N. Engl. J. Med. 1997 Jun;336(24):1713-20; ​DuatRodriguez A et al.AnPediatr(Barc). 2015 Sep;83(3):173-82<span style="background-color:initial">). In addition to the clinical information 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).<span style="background-color:initial">This mutation is also known as p.R1513* (c.4537C>T) in published literature.
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000206013	SCV000782027	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000255589	SCV000842891	pathogenic	not provided	2017-12-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000999744	SCV000885838	pathogenic	not specified	2019-06-09	criteria provided, single submitter	clinical testing	The NF1 c.4600C>T; p.Arg1534Ter variant (rs760703505), also known as c.4537C>T; p.Arg1513Ter, is reported in the medical literature in several individuals affected with neurofibromatosis type 1 (Fahsold 2000, Hutter 2016, Jeong 2006, Ko 2013, Side 1997, Valero 2011). This reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 220152), and only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and 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: Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Hutter S et al. No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients. Hum Genet. 2016 May;135(5):469-75. Jeong SY et al. The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J Korean Med Sci. 2006 Feb;21(1):107-12. 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. Side L et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med. 1997 Jun 12;336(24):1713-20. Valero MC et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011 Mar;13(2):113-22.
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009595	SCV001169696	pathogenic	Neurofibromatosis, type 1; Tibial pseudoarthrosis	2018-11-10	criteria provided, single submitter	research
Medical Genetics, University of Parma	RCV000206013	SCV001218923	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000206013	SCV001426919	pathogenic	Neurofibromatosis, type 1	2020-07-16	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.4537C>T (p.Arg1513X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251346 control chromosomes (gnomAD). The variant, c.4537C>T, had been reported as a recurring pathogenic variant in several individuals affected with Neurofibromatosis Type 1 (e.g. Side_1997, Frayling_2019, Yao_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000206013	SCV000692355	pathogenic	Neurofibromatosis, type 1	2017-05-18	no assertion criteria provided	clinical testing