Submissions for variant NM_001042492.3(NF1):c.1541_1542del (p.Gln514fs)

gnomAD frequency: 0.00001  dbSNP: rs267606600

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164295	SCV000214925	pathogenic	Hereditary cancer-predisposing syndrome	2014-07-10	criteria provided, single submitter	clinical testing	The c.1541_1542delAG pathogenic mutation, located in coding exon 14 of the NF1 gene, results from a deletion of two nucleotides between nucleotide positions 1541 and 1542, causing a translational frameshift with a predicted alternate stop codon. <span style="background-color:initial">This mutation has been described to occurde novoin several NF1 patients in the literature, indicating the recurrent nature of this mutation (Ars E et al. J. Med. Genet. 2003 Jun;40(6):e82 and Robinson et al.Hum. Mutat.<span style="background-color:initial">1996 ;7(1):85-8<span style="background-color:initial">).<span style="background-color:initial"><span style="background-color:initial">In addition to the clinical data presented in the literature, s<span style="background-color:initial">ince 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).
GeneDx	RCV000414730	SCV000491047	pathogenic	not provided	2022-06-07	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22155606, 28891274, 28152038, 30104415, 32581362, 19738042, 8664912, 21354044, 27838393, 14722917, 24676424, 19142971, 26969325, 28955729, 29849115, 29909963, 25788518, 18546366, 29079545, 27284375, 31201679, 31717729, 32575496, 31370276, 33443663, 31776437)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000374	SCV000542104	pathogenic	Neurofibromatosis, type 1	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln514Argfs*43) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 8664912, 17311297, 17914445, 18546366, 25788518, 26969325). ClinVar contains an entry for this variant (Variation ID: 346). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000000374	SCV000781914	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Academic Department of Medical Genetics, University of Cambridge	RCV000164295	SCV000992222	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001001	SCV001158107	pathogenic	not specified	2019-01-05	criteria provided, single submitter	clinical testing	The NF1 c.1541_1542delAG; p.Gln514fs variant (rs267606600) is reported in the medical literature in individuals and families affected with neurofibromatosis type 1 (Anastasaki 2015, Anastasaki 2017, Ars 2003, Brems 2009, De Schepper 2008, Hutter 2016, Lin 2018, Noe 2018, Ponti 2016, Pros 2008, Robinson 1996, Wang 2018, Whitworth 2018, Wimmer 2007). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 346), and is 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 deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Gln514fs variant is considered to be pathogenic. References: Anastasaki C et al. Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning. Hum Mol Genet. 2015 Jun 15;24(12):3518-28. Anastasaki C et al. Children with 5'-end NF1 gene mutations are more likely to have glioma. Neurol Genet. 2017 Sep 22;3(5):e192. Ars E et al. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet. 2003 Jun;40(6):e82. Brems H et al. Glomus tumors in neurofibromatosis type 1: genetic, functional, and clinical evidence of a novel association. Cancer Res. 2009 Sep 15;69(18):7393-401. De Schepper S et al. Somatic mutation analysis in NF1 cafe au lait spots reveals two NF1 hits in the melanocytes. J Invest Dermatol. 2008 Apr;128(4):1050-3. 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. Lin F et al. THSD7A-associated membranous nephropathy in a patient with neurofibromatosis type 1. Eur J Med Genet. 2018 Feb;61(2):84-88. Noe M et al. Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1. Mod Pathol. 2018 Oct;31(10):1532-1538. Ponti G et al. Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report. Oncol Lett. 2016 Jun;11(6):3709-3714. 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. Robinson PN et al. Recurrent 2-bp deletion in exon 10c of the NF1 gene in two cases of von Recklinghausen neurofibromatosis. Hum Mutat. 1996;7(1):85-8. Wang X et al. Breast cancer risk and germline genomic profiling of women with neurofibromatosis type 1 who developed breast cancer. Genes Chromosomes Cancer. 2018 Jan;57(1):19-27. Whitworth J et al. Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. Am J Hum Genet. 2018 Jul 5;103(1):3-18. 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.
Medical Genetics, University of Parma	RCV000000374	SCV001218916	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000414730	SCV001247184	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	NF1: PVS1, PS2
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000000374	SCV001370036	pathogenic	Neurofibromatosis, type 1	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000414730	SCV001470146	pathogenic	not provided	2020-08-27	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000000374	SCV001479025	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000000374	SCV001786623	pathogenic	Neurofibromatosis, type 1	2021-02-04	criteria provided, single submitter	clinical testing	The NF1 c.1541_154delAG (p.Gln514ArgfsTer43) variant is a recurrent deletion predicted to result in a frameshift and premature termination or absence of the protein. Across a selection of the available literature, the p.Gln514ArgfsTer43 variant has been identified in at least eight affected individuals in a heterozygous state (Robinson et al. 1996; Sabbagh et al. 2013; Cali et al. 2017). This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the predicted truncating nature of the variant and application of ACMG criteria, the p.Gln514ArgfsTer43 variant is classified as pathogenic for neurofibromatosis, type 1.
Athena Diagnostics	RCV000414730	SCV001879389	pathogenic	not provided	2020-08-27	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000000374	SCV001976834	pathogenic	Neurofibromatosis, type 1	2021-10-05	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Revvity Omics, Revvity	RCV000414730	SCV002018306	pathogenic	not provided	2021-10-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000000374	SCV002561675	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics, University of Zurich	RCV000000374	SCV002569047	pathogenic	Neurofibromatosis, type 1	2022-05-12	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288457	SCV002580232	pathogenic	Neurofibromatosis-Noonan syndrome	2021-10-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460399	SCV004198232	pathogenic	Juvenile myelomonocytic leukemia	2023-10-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000414730	SCV004227795	pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	PP4, PM2, PM6_supporting, PS4_moderate, PVS1
OMIM	RCV000000374	SCV000020518	pathogenic	Neurofibromatosis, type 1	1996-01-01	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000414730	SCV001955092	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000414730	SCV001963873	pathogenic	not provided		no assertion criteria provided	clinical testing