Submissions for variant NM_001042492.3(NF1):c.7549C>T (p.Arg2517Ter)

dbSNP: rs866445127

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218957	SCV000274026	pathogenic	Hereditary cancer-predisposing syndrome	2015-02-18	criteria provided, single submitter	clinical testing	The p.R2517* pathogenic mutation (also known as c.7549C>T) located in coding exon 51 of the NF1 gene, results from a C to T substitution at nucleotide position 7549. This changes the amino acid from an arginine to a stop codon within coding exon 51. This mutation (reported as R2496X) has been detected in an individual with sporadic NF1 (Purandare S et al, Hum. Mol. Genet. 1994 Jul; 3(7):1109-15). In addition to the clinical data presented in the literature, since premature stop codons 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).
Invitae	RCV000457951	SCV000541947	pathogenic	Neurofibromatosis, type 1	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2496*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 7981679, 10712197, 16835897, 22965773, 25324867). This variant is also known as p.Arg2517*. ClinVar contains an entry for this variant (Variation ID: 230467). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000505900	SCV000604508	pathogenic	not specified	2016-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000579098	SCV000680726	pathogenic	not provided	2020-08-03	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 7981679, 27838393, 30530636, 25525159, 25324867, 26056819, 9783703, 10862084, 27930734, 18041031, 10712197, 11857752, 28135719, 22965773, 16835897, 18546366, 15060124, 29415745, 23460398, 10678181, 31766501, 30098238, 31776437)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000457951	SCV000782105	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000457951	SCV000917894	pathogenic	Neurofibromatosis, type 1	2018-05-25	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.7486C>T (p.Arg2496X) results in a premature termination codon, predicted to cause a truncation of the encoded protein (12%) or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 121268 control chromosomes. The c.7486C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1, both in sporadic and familial cases. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001836756	SCV000927087	pathogenic	Abnormality of the skin	2021-07-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000579098	SCV001334647	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000457951	SCV001479109	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000579098	SCV001879403	pathogenic	not provided	2021-01-26	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. 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 with clinical features associated with this gene. In some published literature, this variant is referred to as c.7549C>T; p.R2517X.
Genome-Nilou Lab	RCV000457951	SCV002560579	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics, University of Zurich	RCV000457951	SCV002569046	pathogenic	Neurofibromatosis, type 1	2022-05-11	criteria provided, single submitter	clinical testing
3billion	RCV000457951	SCV002573296	pathogenic	Neurofibromatosis, type 1	2022-09-01	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%). Stop-gained (nonsense) is 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: VCV000230467 / PMID: 7981679). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000457951	SCV002580805	pathogenic	Neurofibromatosis, type 1	2022-03-14	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000457951	SCV002604943	pathogenic	Neurofibromatosis, type 1	2022-11-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000579098	SCV002774393	pathogenic	not provided	2021-01-26	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of NF1 protein synthesis. In addition, it has been reported in individuals affected with Neurofibromatosis type 1 in the published literature (PMIDs: 29415745 (2018), 25324867 (2014), 22965773 (2012), 16835897 (2006), 10712197 (2000), 9783703 (1998), and 7981679 (1994)). Based on the available information, this variant is classified is pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002494586	SCV002779142	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-03-11	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000457951	SCV004015244	pathogenic	Neurofibromatosis, type 1	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2496*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD). This variant has been reported in individuals with neurofibromatosis type 1 (PMID: 25324867, 7981679, 22965773, 10712197, 16835897). This variant is also known as p.Arg2517* in the literature. ClinVar contains an entry for this variant (Variation ID: 230467) with 14 submissions. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). Therefore, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003469003	SCV004190784	pathogenic	Juvenile myelomonocytic leukemia	2022-10-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000579098	SCV004224761	pathogenic	not provided	2023-01-16	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003595895	SCV004244665	pathogenic	NF1-related disorder	2023-10-30	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2, PM6
GenomeConnect, ClinGen	RCV000457951	SCV000986762	not provided	Neurofibromatosis, type 1		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 02/09/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000579098	SCV001955895	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000579098	SCV001975568	pathogenic	not provided		no assertion criteria provided	clinical testing