Submissions for variant NM_001042492.3(NF1):c.1466A>G (p.Tyr489Cys)

gnomAD frequency: 0.00001  dbSNP: rs137854557

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000000382	SCV000218980	pathogenic	Neurofibromatosis, type 1	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 489 of the NF1 protein (p.Tyr489Cys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs137854557, gnomAD 0.007%). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 10543400, 10607834, 10862084, 11258625, 19076627, 22155606, 22190595). ClinVar contains an entry for this variant (Variation ID: 354). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. Studies have shown that this missense change results in skipping of 62 nucleotides in exon 13 (referred to as exon 10b in the literature) and introduces a premature termination codon (PMID: 10543400, 10607834, 11258625). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492667	SCV000581253	pathogenic	Hereditary cancer-predisposing syndrome	2014-07-11	criteria provided, single submitter	clinical testing	The p.Y489C pathogenic mutation (also known as c.1466A>G), located in coding exon 13 of the NF1 gene, results from an A to G substitution at nucleotide position 1466. This is a recurrent mutation that has been detected in multiple cohorts of NF1 patients (<span style="background-color: initial;">Messiaen LM et al. Genet. Med. 1999; 1(6):248-53,<span style="background-color: initial;">Nemethova M et al. Ann. Hum. Genet. 2013 Sep; 77(5):364-79, Ko JM et al. Pediatr. Neurol. 2013 Jun; 48(6):447-53). Messiaen et al (1999) first described this mutation in 5 patients meeting NIH criteria for NF1 and demonstrated that this alteration creates a novel splice site, resulting in skipping of the last 62 nucleotides of coding exon 13 and truncation of the protein. In Nemethova et al (2013), this mutation was observed to segregate with disease in a patient meeting NIH criteria for NF1 and her twin daughters, in whom cafe au lait spots and axial/inguinal freckling were present in infancy. Functional studies performed in this study were also consistent with a splicing defect resulting in a truncated protein. Based on the available evidence, p.Y489C is classified as a pathogenic mutation.
Medical Genetics, University of Parma	RCV000000382	SCV000588721	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000000382	SCV000678216	pathogenic	Neurofibromatosis, type 1	2017-08-01	criteria provided, single submitter	clinical testing	NF1 NM_001042492.2 exon1 p.Tyr489Cys (c.1466A>G): This variant has been reported in >10 individuals with Neurofibromatosis type 1 (NF1), including 1 individual in which this variant was de novo (Messiaen 1999 PMID: 11258625, Ars 2000 PMID:10607834, Messiaen 2000 PMID:10862084, Bongiomo 2008 PMID:19076627, Laycock-van Spyk 2011 PMID:22155606, Ribeiro 2012 PMID:22190595, Laurito 2015 PMID:25919870, Zhang 2015 PMID:26056819). This variant segregated with disease in 2 affected family members (Ars 2000 PMID:10607834). This variant is present in 3/245628 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs137854557). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar (Variation ID:354). Evolutionary conservation and computational predictive tools for this variant are unclear. Of note, functional studies have shown a deleterious effect of this variant, resulting in the creation of a new splice site (Messiaen 1999 PMID: 11258625, Ars 2000 PMID:10607834, Messiaen 2000 PMID:10862084). In summary, this variant is classified as pathogenic based on the data above (presence of this variant in affected probands, presence as a de novo and predicted impact to protein).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000000382	SCV000781908	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757556	SCV000885830	pathogenic	not provided	2017-07-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000000382	SCV001140344	pathogenic	Neurofibromatosis, type 1	2020-01-23	criteria provided, single submitter	clinical testing
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009573	SCV001169674	pathogenic	Neurofibromatosis, type 1; Tibial pseudarthrosis	2018-11-10	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000000382	SCV001368991	pathogenic	Neurofibromatosis, type 1	2019-01-08	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PS4,PP4,PP5.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000000382	SCV001440184	pathogenic	Neurofibromatosis, type 1	2019-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000757556	SCV001470145	pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing	Peer-reviewed experimental studies have demonstrated that this variant causes aberrant splicing resulting in a nonsense variant (p.Tyr489*) in the NF1 mRNA which causes premature termination of NF1 protein synthesis (PMID: 10543400 (1999), 11258625 (1999), and 10607834 (2000)). It has been reported in numerous Neurofibromatosis type 1 patients in the published literature (PMID: 23758643 (2013), 23668869 (2013), and 26740943 (2015)). Based on the available information, this variant is classified as pathogenic.
Athena Diagnostics	RCV000757556	SCV001476702	pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals and families with NF1. In some published literature, this variant is referred to as 1466del62. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10543400, 11258625, and 10607834)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000000382	SCV001478918	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813925	SCV001755402	pathogenic	Abnormality of the skin	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000757556	SCV001772211	pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing	Exonic splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Osborn and Upadhyaya, 1999; Messiaen et al., 2000; Nemethova et al., 2013); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29685074, 26056819, 12807981, 10862084, 10543400, 31533797, 34694046, 29922827, 34427956, 11258625, 10607834, 24803665, 25919870, 11258624, 12095621, 27074763, 19076627, 11735023, 23758643, 22155606, 15863657, 22190595, 15994866, 29666462, 29522274, 12566521, 30014477, 30290804, 30308447, 23668869, 30530636, 31766501, 31717729, 31370276, 29625052, 33372952, 31589614, 31776437, 34308104, 34945792, 33999308, 34992632)
3billion	RCV000000382	SCV002058269	pathogenic	Neurofibromatosis, type 1	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000354, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 10607834, 10862084, 10543400, 22155606, 19076627, PS4_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000000382	SCV002512199	pathogenic	Neurofibromatosis, type 1	2021-09-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 moderate, PP2 supporting, PP4 supporting
Genome-Nilou Lab	RCV000000382	SCV002561668	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics, University of Zurich	RCV000000382	SCV002569065	pathogenic	Neurofibromatosis, type 1	2022-05-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504731	SCV002798755	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-12-14	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000000382	SCV003919714	pathogenic	Neurofibromatosis, type 1	2023-04-26	criteria provided, single submitter	clinical testing
Suma Genomics	RCV000000382	SCV004037037	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460400	SCV004198346	pathogenic	Juvenile myelomonocytic leukemia	2023-08-25	criteria provided, single submitter	clinical testing
OMIM	RCV000000382	SCV000020526	pathogenic	Neurofibromatosis, type 1	2003-02-01	no assertion criteria provided	literature only
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257527	SCV001434353	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000757556	SCV001955347	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000757556	SCV001968585	pathogenic	not provided		no assertion criteria provided	clinical testing