Submissions for variant NM_001042492.3(NF1):c.3457_3460del (p.Leu1153fs)

dbSNP: rs1321848637

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165479	SCV000216210	pathogenic	Hereditary cancer-predisposing syndrome	2014-08-20	criteria provided, single submitter	clinical testing	The c.3457_3460delCTCA pathogenic mutation, located in coding exon 26 of the NF1 gene, results from a deletion of 4 nucleotides between nucleotide positions 3457 and 3460, causing a translational frameshift with a predicted alternate stop codon.<span style="background-color: initial;">This alteration has been reported in multiple unrelated patients with a clinical diagnosis of NF1, including an individual with NF1 and a malignant peripheral nerve sheath tumor diagnosed at age 25 (<span style="background-color: initial;">Pros E, Hum. Mutat. 2008 Sep; 29(9):E173-93. Kluwe L, Hum. Mutat. 2003 Nov; 22(5):420. Ponti G, Hered Cancer Clin Pract<span style="background-color: initial;">2011; 9:6)<span style="background-color: initial;">. In addition to the clinical data presented in the literature, s<span style="background-color: initial;">ince frameshifts 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).
Invitae	RCV000168453	SCV000219150	pathogenic	Neurofibromatosis, type 1	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1153Metfs*4) 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: 9003501, 14517963, 18546366, 21838856, 25541118, 26969325). ClinVar contains an entry for this variant (Variation ID: 185963). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Medical Genetics, University of Parma	RCV000168453	SCV000588761	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000168453	SCV000781986	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712406	SCV000842889	pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000712406	SCV001168586	pathogenic	not provided	2022-08-05	criteria provided, single submitter	clinical testing	Frameshift 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 in large population cohorts (gnomAD); Also known as 3456delACTC; This variant is associated with the following publications: (PMID: 23668869, 29483232, 18546366, 9003501, 14517963, 29849115, 25541118, 21838856, 24922668, 29146900, 30098238, 31776437, 31717729, 33726816, 33674644, 34427956)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000712406	SCV001446556	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000168453	SCV001479131	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000168453	SCV001571440	pathogenic	Neurofibromatosis, type 1	2021-02-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000712406	SCV001961672	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV001800492	SCV002047379	pathogenic	Abnormal lymph node morphology; Increased nuchal translucency; Cervical lymphadenopathy	2021-12-13	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM1,PM2,PP5
Sema4, Sema4	RCV000165479	SCV002527511	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-03	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000168453	SCV002557495	pathogenic	Neurofibromatosis, type 1	2022-02-02	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 with neurofibromatosis type 1 (NF1; MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. A child can be more severely affected than the carrier parent (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 NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported multiple times as pathogenic in ClinVar and it has been identified in individuals with NF1 (PMID: 31776437). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV000168453	SCV002559962	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468744	SCV004190775	pathogenic	Juvenile myelomonocytic leukemia	2022-12-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000712406	SCV004222165	pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with neurofibromatosis 1 (PMID: 9003501 (1997), 18546366 (2008), 21838856 (2011), 31776437 (2020), 34427956 (2022)) and breast cancer (PMID: 33471991 (2021)). The variant has also been reported in a pediatric case of soft tissue sarcoma (PMID: 33674644 (2021)). Based on the available information, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004552910	SCV004749899	pathogenic	NF1-related disorder	2024-02-28	criteria provided, single submitter	clinical testing	The NF1 c.3457_3460delCTCA variant is predicted to result in a frameshift and premature protein termination (p.Leu1153Metfs*4). This variant has previously been reported in individuals with neurofibromatosis type 1 (referred to as 3456delACTC, Upadhyaya et al. 1997. PubMed ID: 9003501; Table 4, Noë et al. 2018. PubMed ID: 29849115; Warejko et al. 2018. PubMed ID: 29483232; Yao et al. 2019. PubMed ID: 31717729). 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/185963/). Frameshift variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.