Submissions for variant NM_001042492.3(NF1):c.7909C>T (p.Arg2637Ter)

dbSNP: rs786201367

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163482	SCV000214039	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-04	criteria provided, single submitter	clinical testing	The p.R2637* pathogenic mutation (also known as c.7909C>T), located in coding exon 54 of the NF1 gene, results from a C to T substitution at nucleotide position 7909. This changes the amino acid from an arginine to a stop codon within coding exon 54. This pathogenic mutation has been described in an individual who presented with classic cutaneous involvement and plexiform neurofibromas (Upadhyaya M et al. J. Med. Genet. 1995; 32:706-10). In addition, this alteration was also found in an affected patient presenting with Cafe-au-Lait spots, axillary freckling, nodular neurofibromas, lisch nodules and scoliosis (De Luca A et al. Hum. Mutat. 2004; 23:629). 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 mutation is also known as p.R2616* and c.7846C>T in the literature.
UCLA Clinical Genomics Center, UCLA	RCV000196216	SCV000255422	likely pathogenic	Neurofibromatosis, type 1	2013-04-30	criteria provided, single submitter	clinical testing
Invitae	RCV000196216	SCV000541988	pathogenic	Neurofibromatosis, type 1	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2616*) 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 individuals with neurofibromatosis type 1 (PMID: 8544190, 10712197, 15146469, 25074460, 25326637, 27838393). ClinVar contains an entry for this variant (Variation ID: 184261). RNA analysis provides insufficient evidence to determine the effect of this variant on NF1 splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515434	SCV000611289	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2017-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000599610	SCV000709955	pathogenic	not provided	2021-11-18	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: 25525159, 25074460, 10543400, 29872864, 31551924, 26758488, 26962827, 8544190, 10712197, 15146469, 27838393, 25326637, 29158289, 28152038, 16773574, 16544997, 30530636, 12522551, 31776437, 30612635, 31730495, 31533797)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000196216	SCV000782115	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000196216	SCV000915756	pathogenic	Neurofibromatosis, type 1	2018-09-06	criteria provided, single submitter	clinical testing	The NF1 c.7846C>T (p.Arg2616Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg2616Ter variant has been reported in at least nine studies and is found in at least 25 probands in a heterozygous state (Upadhyaya et al. 1995; Osborn et al. 1999; Fahsold et al. 2000; Wang et al. 2003; De Luca et al. 2004; Shirinzi et al. 2006; Stevenson et al. 2006; Messiaen and Wimmer 2008; Vuralli et al. 2016). Two probands were related and had clinical features of NF1 and neurofibromatosis-Noonan syndrome. The p.Arg2616Ter variant was absent from 152 controls (De Luca et al. 2004; Shirinzi et al. 2006) and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or Genome Aggregation Database. Due to the potential impact of stop-gained variants and the evidence in the literature, the p.Arg2616Ter variant is classified as pathogenic for NF1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009586	SCV001169687	pathogenic	Neurofibromatosis, type 1; Tibial pseudarthrosis	2018-11-10	criteria provided, single submitter	research
Medical Genetics, University of Parma	RCV000196216	SCV001218931	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000196216	SCV001478917	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000599610	SCV001961677	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
3billion	RCV001808436	SCV002058639	pathogenic	Neurofibromatosis-Noonan syndrome	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000184261, PMID:8544190, 3billion dataset).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000196216	SCV002061467	pathogenic	Neurofibromatosis, type 1	2021-07-21	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
Genome-Nilou Lab	RCV000196216	SCV002560593	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000196216	SCV002579301	pathogenic	Neurofibromatosis, type 1	2021-07-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196216	SCV003800700	pathogenic	Neurofibromatosis, type 1	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.7846C>T (p.Arg2616X) 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. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 251314 control chromosomes (gnomAD). c.7846C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (e.g. Upadhyaya_1995, De Luca_2004, Sabbagh_2013, Zhu_2019). These data indicate that the variant is very likely to be associated with disease. Fifteen submitters have provided 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000196216	SCV003839053	pathogenic	Neurofibromatosis, type 1	2022-09-22	criteria provided, single submitter	clinical testing	c.7909C>T in NF1 has been reported in multiple unrelated individuals with Neurofibromatosis type 1 including as a de novo occurrence. It has also been reported in a parent and child with Neurofibromatosis-Noonan syndrome. The variant (rs786201367) is absent from a large population dataset and has been reported in ClinVar (Variation ID 184261). This nonsense variant results in a premature stop codon in exon 54 of 58, likely leading to nonsense-mediated decay and lack of protein production. We consider c.7909C>T in NF1 to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004551398	SCV004120577	pathogenic	NF1-related disorder	2023-07-18	criteria provided, single submitter	clinical testing	The NF1 c.7909C>T variant is predicted to result in premature protein termination (p.Arg2637*). This variant, also referred to as c.7846C>T (p.Arg2616*), has been reported in multiple individuals with neurofibromatosis type 1 (Upadhyaya. 1995. PubMed ID: 8544190; Vuralli. 2016. PubMed ID: 26758488; Zhu. 2016. PubMed ID: 26962827; Table S3 - LaDuca. 2017. PubMed ID: 28152038; Gieldon. 2018. PubMed ID: 29158289). Loss-of-function variants in NF1 are known to be pathogenic (Fahsold. 2000 et al. PubMed ID: 10712197). 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/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184261/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003462120	SCV004198334	pathogenic	Juvenile myelomonocytic leukemia	2023-09-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000196216	SCV004806252	pathogenic	Neurofibromatosis, type 1	2024-03-25	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000196216	SCV000692369	pathogenic	Neurofibromatosis, type 1	2015-08-28	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000196216	SCV003927856	pathogenic	Neurofibromatosis, type 1	2023-04-01	no assertion criteria provided	clinical testing