Submissions for variant NM_001042492.3(NF1):c.1721+3A>G

dbSNP: rs1057518904

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414938	SCV000492873	pathogenic	Cafe au lait spots, multiple; Neurofibroma	2014-12-01	criteria provided, single submitter	clinical testing
Invitae	RCV000457496	SCV000542219	pathogenic	Neurofibromatosis, type 1	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 15 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 individuals with neurofibromatosis type 1 (PMID: 7981679, 15146469, 16944272, 18546366, 23404336, 26478990). This variant is also known as c.1720+3A>G. ClinVar contains an entry for this variant (Variation ID: 374108). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 15 and introduces a premature termination codon (PMID: 7981679; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492226	SCV000581237	pathogenic	Hereditary cancer-predisposing syndrome	2015-04-06	criteria provided, single submitter	clinical testing	The c.1721+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 15 in the NF1 gene. This mutation was shown by twoseparate studiestoinduce skipping ofexon11 at the mRNA level, causinga shift in the translational reading frame, leading to premature truncation of the NF1protein(p.Ala548LeufsX13) (PurandareSM, et al. Hum. Mol. Genet. 1994;3(7):1109-15 andPros E, et al. Hum.Mutat. 2008;29(9):E173-93). This mutation has been seen in four individuals who fulfill the NIH diagnostic criteria for NF1 (neurofibromatosis type 1) and in nine individualssuspected of having aNF1 clinical diagnosis. In addition, one of these individuals presented withfeatures of bothNF1 and Noonan syndrome (De Luca A, et al. Am. J. Hum. Genet. 2005;77(6):1092-101,Griffiths S, et al. Fam. Cancer 2007;6(1):21-34,Violante IR, et al. Brain 2013;136(Pt 3):918-25,Purandare SM, et al. Hum. Mol. Genet. 1994;3(7):1109-15,FahsoldR, et al. Am. J. Hum. Genet. 2000;66(3):790-818,andArs E, et al. Hum. Mol. Genet. 2000;9(2):237-47).Based on the available evidence, c.1721+3A>G is classified as a pathogenic mutation.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626641	SCV000747343	pathogenic	Cafe au lait spots, multiple; Optic nerve glioma	2017-01-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000992429	SCV001144735	pathogenic	not provided	2019-08-06	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/263140 chr). Variant has been found in 6 or more unrelated symptomatic patients, while absent in large general pop studies. Predicted to negatively affect a known splice site. Damaging to protein function(s) relevant to disease mechanism. Inconclusive segregation with disease.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000457496	SCV001499690	pathogenic	Neurofibromatosis, type 1	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000992429	SCV002013467	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in skipping of exon 11 (Violante et al., 2013; Esposito et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing; Also known as IVS15+3A>G; This variant is associated with the following publications: (PMID: 19845691, 26478990, 7981679, 23404336, 18546366, 26056819, 15146469, 28008555, 10607834, 16944272, 26969325, 10712197, 16380919, 32352596, 31713330, 31370276, 31776437)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000457496	SCV002061704	pathogenic	Neurofibromatosis, type 1	2021-11-16	criteria provided, single submitter	clinical testing	PS3, PS4, PP3, PM2
Genome-Nilou Lab	RCV000457496	SCV002561697	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000457496	SCV002567805	pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470366	SCV004190803	pathogenic	Juvenile myelomonocytic leukemia	2022-07-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000457496	SCV005077300	pathogenic	Neurofibromatosis, type 1	2024-04-08	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.1721+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, resulting in exon skipping leading to a frameshift (Purandare_1994, Pros_2008). The variant was absent in 225584 control chromosomes (gnomAD). c.1721+3A>G has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (e.g. Purandare_1994, De Luca_2004, Griffiths_2006, Pros_2008.) These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 7981679, 15146469, 16944272, 18546366). ClinVar contains an entry for this variant (Variation ID: 374108). Based on the evidence outlined above, the variant was classified as pathogenic.