Submissions for variant NM_001042492.3(NF1):c.3916C>T (p.Arg1306Ter)

dbSNP: rs376576925

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457194	SCV000542202	pathogenic	Neurofibromatosis, type 1	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1306*) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 9783703, 10712197, 15146469, 16835897, 16944272, 26969325). ClinVar contains an entry for this variant (Variation ID: 404592). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000489457	SCV000577115	pathogenic	not provided	2022-01-21	criteria provided, single submitter	clinical testing	Nonsense 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 (Park 1998); This variant is associated with the following publications: (PMID: 31066482, 28955729, 31533797, 32164600, 25525159, 16835897, 16944272, 10712197, 15146469, 12112660, 11735023, 12552569, 22155606, 26969325, 30530636, 29957862, 9783703, 30308447, 31347283, 31370276, 30877234, 29625052, 27535533, 31776437, Krat[case reeport], 33593231, 34694046)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000457194	SCV000782006	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000489457	SCV000927881	pathogenic	not provided	2018-08-24	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000457194	SCV001156511	pathogenic	Neurofibromatosis, type 1	2020-02-03	criteria provided, single submitter	clinical testing
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009594	SCV001169695	pathogenic	Neurofibromatosis, type 1; Tibial pseudarthrosis	2018-11-10	criteria provided, single submitter	research
Ambry Genetics	RCV002318998	SCV001183047	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-02-23	criteria provided, single submitter	clinical testing	The p.R1306* pathogenic mutation (also known as c.3916C>T), located in coding exon 29 of the NF1 gene, results from a C to T substitution at nucleotide position 3916. This changes the amino acid from an arginine to a stop codon within coding exon 29. This mutation has been detected in several individuals, once as a de novo occurrence, meeting NIH diagnostic criteria for Neurofibromatosis type 1 (NF1) (Marwaha A et al. Br. J. Dermatol., 2018 Nov;179:1216-1217, Tsipi M et al. J. Neurol. Sci., 2018 Dec;395:95-105).Park VM et al. J. Med. Genet., 1998 Oct;35:813-20; Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; Lee MJ et al. Hum Mutat. 2006 Aug;27(8):832; Hutter S et al. Hum Genet. 2016 May;135(5):469-75). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000457194	SCV001431876	pathogenic	Neurofibromatosis, type 1	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.3916C>T (p.Arg1306X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251422 control chromosomes. c.3916C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (Fahsold_2000, Sabbagh_2013). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathongenic n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000489457	SCV001470147	pathogenic	not provided	2020-05-14	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, 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 found in general population data at a frequency that is consistent with pathogenicity.
Athena Diagnostics	RCV000489457	SCV001476707	pathogenic	not provided	2020-05-14	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, 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 found in general population data at a frequency that is consistent with pathogenicity.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000457194	SCV001479008	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000489457	SCV001746524	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	NF1: PVS1, PM2, PS4:Moderate
Genome-Nilou Lab	RCV000457194	SCV002560006	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000457194	SCV004041021	pathogenic	Neurofibromatosis, type 1	2023-05-02	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000457194	SCV004176958	pathogenic	Neurofibromatosis, type 1	2023-08-27	criteria provided, single submitter	clinical testing	The NF1 c.3916C>T (p.Arg1306Ter) variant was identified at near heterozygous allelic fraction. This variant leads to a premature termination codon, which is predicted to lead to nonsense mediated decay. It has been reported in several individuals affected with neurofibromatosis type 1 (Sabbagh A et al., PMID: 23913538; Chen L et al., PMID: 31347283; Wiest V et al., PMID: 14635100; Thomas L et al., PMID: 22108604; Zhu G et al., PMID: 31533797). This variant has been reported as a somatic variant in 13 cases in the cancer database COSMIC and has been reported in the ClinVar database as pathogenic by 12 submitters (ClinVar ID: 404592). The NF1 c.3916C>T (p.Arg1306Ter) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the NF1 c.3916C>T (p.Arg1306Ter) variant is classified as pathogenic and clinically significant.
Baylor Genetics	RCV003470401	SCV004190748	pathogenic	Juvenile myelomonocytic leukemia	2023-04-14	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000457194	SCV001190825	uncertain significance	Neurofibromatosis, type 1	2020-02-05	no assertion criteria provided	clinical testing