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

dbSNP: rs137854552

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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
Ambry Genetics	RCV004558221	SCV005048263	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-10-14	criteria provided, single submitter	clinical testing	The c.5839C>T (p.R1947*) alteration, located in exon 39 (coding exon 39) of the NF1 gene, consists of a C to T substitution at nucleotide position 5839. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1947. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation (also known as p.R1968* (c.5902C>T) in the NM_001042492 isoform) has been described as a recurring mutation in individuals meeting diagnostic criteria for Neurofibromatosis type 1 (NF1) (Cawthon, 1990; Fahsold, 2000; Ars, 2003; Stewart, 2014; Hutter, 2016). In addition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews, 1996). Based on the available evidence, this alteration is classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000418287	SCV005196977	pathogenic	not provided	2022-05-27	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
Diagnostics Centre, Carl Von Ossietzky University Oldenburg	RCV004562178	SCV005049561	pathogenic	Neurofibromatosis-Noonan syndrome	2023-10-23	no assertion criteria provided	clinical testing	The variant NF1:c.5839C>T, p.(Arg1968*), which is located in the coding exon 40 of the NF1 gene, results from a cytosine-to-thymine substitution at nucleotide position c.5839. The arginine at protein position 1968 is replaced by a stop codon at the translational level. The variant affects and exon (40/58) that is present in biologically relevant transcripts and is predicted to cause protein truncation/absent due to non-sense mediated decay.The variant is classified as rare in the overall population (allele frequency= 0.000001859 in gnomAD v4.1.0). The variant has been consistenly classified as Pathogenic on 17 entries in ClinVar (ClinVarID: 343). In several publications, the variant has been reported as causative for neurofibromatosis (PMID: 2114220, 7649559, 12807981,10076878). Similar to previous report, the variant was detected de novo. In summary, the variant is classified as Pathogenic.