ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2041C>T (p.Arg681Ter) (rs768638173)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168265 SCV000218936 pathogenic Neurofibromatosis, type 1 2020-10-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg681*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in several individuals affected with neurofibromatosis type 1 (PMID: 10607834, 23404336, 25324867). ClinVar contains an entry for this variant (Variation ID: 188280). 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 RCV000414746 SCV000491216 pathogenic not provided 2018-03-19 criteria provided, single submitter clinical testing The R681X nonsense variant in the NF1 gene has been reported previously in association with neurofibromatosis type 1 (Ars et al., 2000; Maruoka et al., 2014). It is not observed in large population cohorts (Lek et al., 2016). R681X is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, functional studies confirm that this variant significantly reduces expression of the NF1 protein as well as increases ERK levels (Toonen et al., 2016; Li et al., 2016). Therefore, we consider this variant to be pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415426 SCV000492769 pathogenic Cafe-au-lait spot; Axillary freckling; Optic nerve glioma 2015-10-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567277 SCV000674060 pathogenic Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing The p.R681* pathogenic mutation (also known as c.2041C>T), located in coding exon 18 of the NF1 gene, results from a C to T substitution at nucleotide position 2041. This changes the amino acid from an arginine to a stop codon within coding exon 18. This mutation has been identified in several individuals meeting NIH diagnostic criteria for neurofibromatosis type 1 (NF1) (Zafar R et al. Radiol Case Rep, 2016 Mar;11:33-5; Maruoka R et al. Genet Test Mol Biomarkers, 2014 Nov;18:722-35; Ars E et al, Hum. Mol. Genet. 2000 Jan; 9(2):237-47; Violante IR et al. Brain 2013 Mar;136(Pt 3):918-25). In addition, several functional studies have shown that this mutation causes reduced protein expression and can contribute to the development of optic gliomas and neurofibromas (Li K et al. Dis Model Mech, 2016 Jul;9:759-67; Toonen JA et al. Hum. Mol. Genet., 2016 May;25:1703-13; Gutmann DH. Expert Rev Neurother, 2016 Sep;16:999-1001). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000168265 SCV000781937 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999937 SCV000885841 pathogenic not specified 2019-03-28 criteria provided, single submitter clinical testing The NF1 c.2041C>T; p.Arg681Ter variant (rs768638173) is reported in the literature in individuals with neurofibromatosis type 1 (NF1) (Ars 2000, Kim 2014, Violante 2013). Functional analyses show the variant significantly decreases NF1 gene expression and function (Li 2016, Toonen 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 188280), and is found in the general population with a very low allele frequency of 0.0004% (1/245466 alleles) in the Genome Aggregation Database. 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: Ars E et al. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. Hum Mol Genet. 2000 Jan 22;9(2):237-47. Kim MJ et al. Neurofibromatosis type 1: a single center's experience in Korea. Korean J Pediatr.2014 Sep;57(9):410-5. Li K et al. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I. Dis Model Mech. 2016 Jul 1;9(7):759-67. Toonen JA et al. NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1. Hum Mol Genet. 2016 May 1;25(9):1703-13. Violante IR et al. GABA deficit in the visual cortex of patients with neurofibromatosis type 1: genotype-phenotype correlations and functional impact. Brain. 2013 Mar;136(Pt 3):918-25.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000168265 SCV001479207 pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000168265 SCV000692343 pathogenic Neurofibromatosis, type 1 2015-10-02 no assertion criteria provided clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001257528 SCV001434354 pathogenic Rhabdomyosarcoma (disease) 2020-09-01 no assertion criteria provided provider interpretation
Human Genetics Research Group,Shri Mata Vaishno Devi University RCV000168265 SCV001762282 pathogenic Neurofibromatosis, type 1 2021-07-29 no assertion criteria provided research In this first report of NF1 from Jammu and Kashmir India, Study of the NF1 family, indicating the autosomal dominant mode of transmission of NM_000267.3:c.2041C>T NF1 variation. In the family, the proband and two of his affected children were found to be heterozygous for the variation, whereas an unaffected child was found without the variation. Further, Affected grand-daughter was found heterozygous where as unaffected grandson was found not carrying the variation. The variation was seen perfectly segregating with the disease in the 3 generational family. Source OMIM: Neurofibromatosis type I (NF1) is caused by heterozygous mutation in the neurofibromin gene (NF1; 613113).

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