Submissions for variant NM_001042492.3(NF1):c.1062+3A>G

dbSNP: rs1057521098

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437730	SCV000521059	likely pathogenic	not provided	2024-11-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); RNA studies demonstrate a damaging effect: loss of in-frame exon 9 (PMID: 32123317; Douben H et al. (2023) Human Mutation. https://onlinelibrary.wiley.com/doi/10.1155/2023/9628049); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 34887416, 33804961, 18546366, 37751797, 34663891, Douben2023[Functional study], 32123317)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000583516	SCV000948669	pathogenic	Neurofibromatosis, type 1	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change falls in intron 9 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 likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 18546366; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381606). 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 9, but is expected to preserve the integrity of the reading-frame (PMID: 18546366, 32123317). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000583516	SCV002561625	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000583516	SCV002567794	likely pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411323	SCV002717364	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-09-14	criteria provided, single submitter	clinical testing	The c.1062+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 9 in the NF1 gene. This alteration has been detected in multiple individuals with a clinical diagnosis or suspicion of neurofibromatosis type 1 (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in skipping of exon 9 (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Wai HA et al. Genet Med, 2020 06;22:1005-1014; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000583516	SCV002819462	pathogenic	Neurofibromatosis, type 1	2024-10-14	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.1062+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. Computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 5' splicing donor site. One predicts the variant weakens this site. One predicts the variant no significant impact on splicing. Publications report experimental evidence that this variant affects mRNA splicing, resulting in an in-frame deletion (r.889_1062del/p.Lys297_Lys354del; Pros_2008, Wai_2020, Douben_2023). The variant allele was found at a frequency of 3.8e-06 in 265890 control chromosomes (gnomAD). c.1062+3A>G has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (Pros_2008, Martorana_2023, Labcorp (formerly Invitae)), and in one case it was reported as a de novo occurrence. These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18546366, 32123317, 33804961, 37751797). ClinVar contains an entry for this variant (Variation ID: 381606). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003470382	SCV004199029	likely pathogenic	Juvenile myelomonocytic leukemia	2021-02-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000437730	SCV005878255	likely pathogenic	not provided	2024-07-22	criteria provided, single submitter	clinical testing	The NF1 c.1062+3A>G variant (rs1057521098; ClinVar ID: 381606) is reported in the literature in an individual affected with a diagnosis or clinical suspicion of neurofibromatosis type 1 (Pros 2008). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Consistent with predictions, functional analyses indicate this variant leads to skipping of exon 9, resulting in the in-frame deletion of 58 amino acids (Pros 2008, Wai 2020). Other variants impacting this splice donor site (c.1062+1G>A, c.1062+1G>C, and c.1062+2T>C) have also been reported in patients with clinical features of neurofibromatosis type 1 and are considered disease-causing (Ars 2003, Bausch 2007, Upadhyaya 1997). Based on the available information, the c.1062+3A>G variant is considered to be likely pathogenic. References: Ars et al. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet. 2003 Jun;40(6):e82. PMID: 12807981. Bausch et al. Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1. J Clin Endocrinol Metab. 2007 Jul;92(7):2784-92. PMID: 17426081. Pros et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008 Sep;29(9):E173-93. PMID: 18546366. Upadhyaya et al. Six novel mutations in the neurofibromatosis type 1 (NF1) gene. Hum Mutat. 1997;10(3):248-50. PMID: 9298829. Wai HA et al. Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance. Genet Med. 2020 Jun;22(6):1005-1014. PMID: 32123317.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583516	SCV000692340	uncertain significance	Neurofibromatosis, type 1	2016-06-03	no assertion criteria provided	clinical testing