Submissions for variant NM_001042492.3(NF1):c.1260+1604A>G

dbSNP: rs1131691067

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492499	SCV000581238	pathogenic	Hereditary cancer-predisposing syndrome	2015-11-05	criteria provided, single submitter	clinical testing	The c.1260+1604A>G intronic pathogenic mutation results from an A to G substitution 1604 nucleotides after coding exon 11 in the NF1 gene.Thismutation has been reported in several individuals withneurofibromatosis type 1 (NF1), one of whom met the NIH clinical diagnostic criteria for NF1.In addition,in vitrostudies havedemonstrated that this alteration affectssplicing and causesan insertion of a crypticexonthat shifts the reading frame, ultimately causing a premature stopcodon(Valero MC et al. J MolDiagn. 2011;13(2):113-122;SabbaghA et al.HumMutat. 2013 Nov;34(11):1510-8). Based on the available evidence, c.1260+1604A>Gis classified as a pathogenic mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816703	SCV000957222	pathogenic	Neurofibromatosis, type 1	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 21354044, 23913538, 27999334; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as IVS9+1604A>G. ClinVar contains an entry for this variant (Variation ID: 428941). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 11115850, 23913538; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Medical Genetics, University of Parma	RCV000816703	SCV001218913	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001726196	SCV001961667	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	NF1: PVS1, PM2, PS4:Moderate, PP4
GeneDx	RCV001726196	SCV002013587	pathogenic	not provided	2022-04-25	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in aberrant splicing leading to protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Valero 2011, Sabbagh 2013, Evans 2016, Wang 2017, Assunto 2019, Giugliano 2019); No data available from ethnically-matched control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 30530636, 31730495, 30104415, 21354044, 31370276, 27999334, 27322474, 23913538, 32486389, 11115850, 28891274, 34782607, 34573290)
Revvity Omics, Revvity	RCV001726196	SCV002018311	pathogenic	not provided	2020-11-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000492499	SCV002527386	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-12	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000816703	SCV002561650	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000816703	SCV002580477	pathogenic	Neurofibromatosis, type 1	2021-12-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002431434	SCV002681946	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-11-29	criteria provided, single submitter	clinical testing	The c.1260+1604A>G intronic pathogenic mutation results from an A to G substitution 1604 nucleotides after coding exon 11 in the NF1 gene. This mutation has been reported in several individuals who met the NIH clinical diagnostic criteria for neurofibromatosis type 1 (NF1) (Wang X et al. Genes Chromosomes Cancer. 2018 Jan;57:19-27; Sabbagh A et al. Hum. Mutat. 2013 Nov;34:1510-8; Evans DG et al. EBioMedicine. 2016 May;7:212-20). In addition, RNA studies have demonstrated that this alteration creates a new acceptor site, leading to an insertion of a cryptic exon that introduces a premature termination codon (Valero MC et al. J Mol Diagn. 2011;13(2):113-122; Sabbagh A et al. Hum Mutat. 2013 Nov;34(11):1510-8; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.