Submissions for variant NM_001042492.3(NF1):c.3721C>T (p.Arg1241Ter)

dbSNP: rs137854562

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129869	SCV000184686	pathogenic	Inborn genetic diseases	2014-06-06	criteria provided, single submitter	clinical testing
Invitae	RCV000000390	SCV000284442	pathogenic	Neurofibromatosis, type 1	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1241*) 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 neurofibromatosis type 1 (PMID: 10712197, 12483293, 16835897, 23668869, 25624686). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 361). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000578991	SCV000680720	pathogenic	not provided	2022-07-05	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: 25049327, 28152038, 22962301, 29620724, 25525159, 12483293, 27236105, 24931142, 31730495, 31717729, 25624686, 10712197, 30530636, 17889038, 26230854, 15060124, 29089047, 16835897, 23668869)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000578991	SCV000884244	pathogenic	not provided	2018-06-08	criteria provided, single submitter	clinical testing	The NF1 c.3721C>T; p.Arg1241Ter variant (rs137854562) is reported in the literature in several individuals with NF1 (Fahsold 2000, Gupta 2015, Ko 2013, Lee 2006, Upadhyaya 2003). This variant is reported as pathogenic in ClinVar (Variation ID: 361). It is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Gupta V et al. Rare case of optic pathway glioma with extensive intra-ocular involvement in a child with neurofibromatosis type 1. Middle East Afr J Ophthalmol. 2015 Jan-Mar;22(1):117-8. Ko JM et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 2013 Jun;48(6):447-53. Lee MJ et al. Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Hum Mutat. 2006 Aug;27(8):832. Upadhyaya M et al. Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1. Hum Genet. 2003 Jan;112(1):12-7.
Medical Genetics, University of Parma	RCV000000390	SCV001218920	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000000390	SCV001429942	pathogenic	Neurofibromatosis, type 1	2019-05-08	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000000390	SCV001479137	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000390	SCV001523053	pathogenic	Neurofibromatosis, type 1	2019-11-14	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing by following sources [PMID: 10712197, 28152038, 25525159, 25624686, 17889038, 29620724, 29089047, 12483293, ClinVar ID: 361]
Revvity Omics, Revvity	RCV000578991	SCV002018302	pathogenic	not provided	2019-03-20	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000000390	SCV002559983	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000000390	SCV002769466	pathogenic	Neurofibromatosis, type 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated juvenile myelomonocytic leukemia (MIM#607785), familial spinal neurofibromatosis (MIM#162210), neurofibromatosis type 1 (MIM#162200), neurofibromatosis-Noonan syndrome (MIM#601321) and Watson syndrome (MIM#193520). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Disease manifestation can be extremely variable, even within a family (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other NMD-predicted variants have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple unrelated individuals with neurofibromatosis type 1 (ClinVar; PMIDs: 16835897, 33919865). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV003466769	SCV004190717	pathogenic	Juvenile myelomonocytic leukemia	2023-05-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000578991	SCV004227861	pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing	PP4, PM2, PM6, PS4_moderate, PVS1
OMIM	RCV000000390	SCV000020534	pathogenic	Neurofibromatosis, type 1	2003-01-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000000390	SCV000692349	pathogenic	Neurofibromatosis, type 1	2015-01-21	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000578991	SCV001742680	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000578991	SCV001964169	pathogenic	not provided		no assertion criteria provided	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000000390	SCV003840164	pathogenic	Neurofibromatosis, type 1		no assertion criteria provided	research