Submissions for variant NM_001042492.3(NF1):c.499_502del (p.Cys167fs)

dbSNP: rs786201874

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164374	SCV000215009	pathogenic	Inborn genetic diseases	2014-06-06	criteria provided, single submitter	clinical testing
Invitae	RCV000461491	SCV000542062	pathogenic	Neurofibromatosis, type 1	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys167Glnfs*10) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is present in population databases (rs786201874, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 10543400, 24294391). This variant is also known as 495delTGTT. ClinVar contains an entry for this variant (Variation ID: 185021). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000486687	SCV000568598	pathogenic	not provided	2022-02-15	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as c.495delTGTT; This variant is associated with the following publications: (PMID: 18546366, 17726231, 17311297, 31533797, 24294391, 22155606, 12807981, 18041031, 10543400, 24676424, 20844836, 23913538, 30293248, 30530636, 28191890, 16835897, 24789688, 27838393, 28152038, 31730495, 30098238, 31370276, 34246755, 31066482)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000461491	SCV000781872	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009588	SCV001169689	pathogenic	Neurofibromatosis, type 1; Tibial pseudarthrosis	2018-11-10	criteria provided, single submitter	research
Ambry Genetics	RCV002318954	SCV001185242	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-09-15	criteria provided, single submitter	clinical testing	The c.499_502delTGTT variant, located in coding exon 5 of the NF1 gene, results from a deletion of 4 nucleotides at nucleotide positions 499 to 502, causing a translational frameshift with a predicted alternate stop codon (p.C167Qfs*10). This mutation has been observed in multiple patients with sporadic or familial NF1 (Osborn MJ and Upadhyaya M. Hum. Genet. 1999 Oct;105:327-32; Toliat MR et al. Electrophoresis. 2000 Feb;21:541-4; Ars E et al. J. Med. Genet. 2003 Jun;40:e82; Schaefer IM et al. Int J Clin Exp Pathol, 2013 Nov;6:3003-8; Uusitalo E et al. Acta Derm. Venereol., 2014 Nov;94:663-6; Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60; Giugliano T et al. Genes (Basel) 2019 07;10(8)). Of note, this mutation is also designated as c.495delTGTT and c.495_498del in published literature. 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.
Medical Genetics, University of Parma	RCV000461491	SCV001218909	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000461491	SCV001369727	pathogenic	Neurofibromatosis, type 1	2019-12-05	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000461491	SCV001479117	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000486687	SCV002018322	pathogenic	not provided	2019-06-11	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000486687	SCV002051719	pathogenic	not provided	2021-01-26	criteria provided, single submitter	clinical testing	PVS1, PM6_Strong, PM2
3billion	RCV000461491	SCV002521060	pathogenic	Neurofibromatosis, type 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000185021 / PMID: 10543400). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000461491	SCV002561580	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000461491	SCV002581655	pathogenic	Neurofibromatosis, type 1	2022-07-27	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000486687	SCV002818205	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486687	SCV004222174	pathogenic	not provided	2013-01-08	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. In the published literature, the variant has been reported in individuals/families with neurofibromatosis 1 (NF1) or with clinical suspicion of NF1 (PMID: 34427956 (2022), 30530636 (2019), 27838393 (2017), 23913538 (2013), 17311297 (2007), 12807981 (2003), 10726756 (2000), 10543400 (1999)). Based on the available information, this variant is classified as pathogenic.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000461491	SCV000692336	pathogenic	Neurofibromatosis, type 1	2014-07-15	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000486687	SCV001744355	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000486687	SCV001974607	pathogenic	not provided		no assertion criteria provided	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000461491	SCV001984500	pathogenic	Neurofibromatosis, type 1	2020-11-11	flagged submission	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000461491	SCV003927843	pathogenic	Neurofibromatosis, type 1	2023-04-01	no assertion criteria provided	clinical testing