Submissions for variant NM_001042492.3(NF1):c.3826C>T (p.Arg1276Ter)

dbSNP: rs199474742

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227284	SCV000284446	pathogenic	Neurofibromatosis, type 1	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1276*) 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 (rs199474742, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 7655472, 10712197, 10862084, 11857752, 16944272, 23668869, 26056819). ClinVar contains an entry for this variant (Variation ID: 237556). For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238903	SCV000296990	pathogenic	not provided	2015-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000238903	SCV000568607	pathogenic	not provided	2023-12-11	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; This variant is associated with the following publications: (PMID: 26056819, 34418705, 34694046, 29922827, 34427956, 30530636, 25541118, 24932921, 21354044, 7655472, 10712197, 12095621, 9003501, 10543400, 10862084, 9180088, 11857752, 16944272, 16690971, 17426081, 19142971, 22155606, 22108604, 23668869, 30290804, 29914388, 29566708, 30014477, 29915382, 31370276, 33372952, 31776437, 23207425)
Ambry Genetics	RCV000492784	SCV000581268	pathogenic	Hereditary cancer-predisposing syndrome	2015-03-09	criteria provided, single submitter	clinical testing	The p.R1276* pathogenic mutation (also known as c.3826C>T) located in coding exon 28 of the NF1 gene, results from a C to T substitution at nucleotide position 3826. This changes the amino acid from an arginine to a stop codon within coding exon 28. This mutation was originally reported in a childwho had multiple cafe au lait spots, but did not fulfill NIH criteria for Neurofibromatosis type 1 (NF1) (Heim RA, et al.Hum. Mol. Genet. 1995;4(6):975-81).In another report, this mutation was identified in two unrelated individuals who met the NIH clinical criteria for NF1 (Valero MC, et al. J Mol Diagn 2011;13(2):113-22).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).
Genetic Services Laboratory, University of Chicago	RCV000227284	SCV000595980	pathogenic	Neurofibromatosis, type 1	2016-04-09	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000227284	SCV000782000	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000227284	SCV001218921	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000238903	SCV001249043	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000227284	SCV001369022	pathogenic	Neurofibromatosis, type 1	2019-03-26	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000227284	SCV001428479	pathogenic	Neurofibromatosis, type 1	2019-01-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000227284	SCV001479009	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV000227284	SCV001810158	pathogenic	Neurofibromatosis, type 1	2021-08-30	criteria provided, single submitter	clinical testing
Suma Genomics	RCV000227284	SCV002543801	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000227284	SCV002555706	pathogenic	Neurofibromatosis, type 1	2022-06-07	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.3826C>T (p.Arg1276X) 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 251202 control chromosomes (gnomAD). c.3826C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (Examples: Valero_2011, Nemethova_2013 and Mao_2018). These data indicate that the variant is very likely to be associated with disease. Fourteen submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000227284	SCV002559994	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000227284	SCV002581687	pathogenic	Neurofibromatosis, type 1	2022-07-22	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000238903	SCV002818244	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469143	SCV004190756	pathogenic	Juvenile myelomonocytic leukemia	2023-03-20	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000227284	SCV005073922	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing	The observed stop gained variant c.3826C>T (p.Arg1276Ter) in NF1 gene has been reported in heterozygous state in multiple individuals affected with Neurofibromatosis Type 1 (Napolitano F et al. 2022; Zhang ZY et al. 2021; Mao B et al. 2018). Loss-of-function variants in NF1 are known to be pathogenic (Sabbagh A et al. 2013). The p.Arg1276Ter variant has allele frequency 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). The nucleotide change c.3826C>T in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000227284	SCV000692350	pathogenic	Neurofibromatosis, type 1	2016-03-09	no assertion criteria provided	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257529	SCV001434355	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000238903	SCV001743457	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000238903	SCV001956567	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000238903	SCV001973817	pathogenic	not provided		no assertion criteria provided	clinical testing