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

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000255589	SCV000885838	pathogenic	not provided	2017-05-16	criteria provided, single submitter	clinical testing	The NF1 c.4600C>T;p.Arg1534Ter (also known as c.4537C>T;p.Arg1513Ter) variant has been published in the medical literature in several individuals with a clinical diagnosis of NF1 (Fahsold 2000, Hutter 2016, Jeong 2006, Ko 2013, Side 1997, Valero 2011). The variant is listed in the ClinVar database (Variation ID: 220152) and the dbSNP variant database (rs760703505) with an allele frequency of 0.0008 percent in the Genome Aggregation Database. This variant introduces a premature termination codon, which is predicted to result in a truncated protein or absent transcript. Considering available information, this variant is classified as 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.
Ambry Genetics	RCV000492716	SCV000581282	pathogenic	Hereditary cancer-predisposing syndrome	2016-01-18	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Athena Diagnostics Inc	RCV000255589	SCV000842891	pathogenic	not provided	2017-12-14	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc	RCV000206013	SCV000782027	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000415187	SCV000492997	likely pathogenic	Multiple cafe-au-lait spots; Thoracic scoliosis; Subcutaneous neurofibromas	2014-09-29	criteria provided, single submitter	clinical testing
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
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.
Invitae	RCV000206013	SCV000260477	pathogenic	Neurofibromatosis, type 1	2018-06-26	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.