Submissions for variant NM_001042492.3(NF1):c.5902C>T (p.Arg1968Ter)

dbSNP: rs137854552

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000000371	SCV000260568	pathogenic	Neurofibromatosis, type 1	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1947*) 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 clinical features of neurofibromatosis type 1 (PMID: 2114220, 7649559, 7903661, 8069310, 8385067, 10076878; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 1087C>T and c.5902C>T (Arg1968Ter). ClinVar contains an entry for this variant (Variation ID: 343). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000418287	SCV000521066	pathogenic	not provided	2022-01-11	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15146469, 16944272, 22913777, 8845843, 9042399, 25525159, 9195229, 24232412, 1757093, 18546366, 12552569, 27322474, 22155606, 7649559, 11015700, 10721668, 7903661, 8385067, 9101300, 2114220, 26969325, 10076878, 21354044, 29178821, 28124441, 19142971, 16117786, 30290804, 31533797, 31370276, 33443663)
Ambry Genetics	RCV000492774	SCV000581242	pathogenic	Hereditary cancer-predisposing syndrome	2014-11-04	criteria provided, single submitter	clinical testing	The p.R1968* pathogenic mutation (also known as c.5902C>T) located in coding exon 40 of the NF1 gene, results from a C to T substitution at nucleotide position 5902. This changes the amino acid from an arginine to a stop codon within coding exon 40. This pathogenic mutation has been described as a recurring mutation in individuals with neurofibromatosis type 1 (Ars E et al. J. Med. Genet. 2003; 40:e82, Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818). In addtition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews JD et al. Hum. Mol. Genet. 1996, 5:503-7). 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). This pathogenic mutation is also known as p.R1947* (c.5839C>T) in the literature.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000000371	SCV000693463	pathogenic	Neurofibromatosis, type 1	2017-08-10	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000418287	SCV000842894	pathogenic	not provided	2018-02-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762995	SCV000893440	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2018-10-31	criteria provided, single submitter	clinical testing
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009602	SCV001169703	pathogenic	Neurofibromatosis, type 1; Tibial pseudarthrosis	2018-11-10	criteria provided, single submitter	research
Medical Genetics, University of Parma	RCV000000371	SCV001218924	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000000371	SCV001479211	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000418287	SCV002545911	pathogenic	not provided	2022-05-01	criteria provided, single submitter	clinical testing	NF1: PVS1, PM2
Genome-Nilou Lab	RCV000000371	SCV002560158	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV000000371	SCV002758612	pathogenic	Neurofibromatosis, type 1	2021-12-06	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PM1, PM2, PS4
PreventionGenetics, part of Exact Sciences	RCV004547450	SCV004120348	pathogenic	NF1-related disorder	2022-09-28	criteria provided, single submitter	clinical testing	The NF1 c.5902C>T variant is predicted to result in premature protein termination (p.Arg1968*). This variant, referred to as c.5839C>T (p.Arg1947*) in an alternate transcript (NM_000267.3), has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Fashold et al. 2000. PubMed ID: 10712197; de Luca et al. 2004. PubMed ID: 15146469). To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/343/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003460398	SCV004199015	pathogenic	Juvenile myelomonocytic leukemia	2021-09-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000000371	SCV004807877	pathogenic	Neurofibromatosis, type 1	2024-03-29	criteria provided, single submitter	clinical testing
OMIM	RCV000000371	SCV000020515	pathogenic	Neurofibromatosis, type 1	2000-01-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000000371	SCV000692361	pathogenic	Neurofibromatosis, type 1	2017-03-03	no assertion criteria provided	clinical testing