Submissions for variant NM_001042492.3(NF1):c.5269-1G>C

dbSNP: rs876660141

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810978	SCV002050237	likely pathogenic	not provided	2021-04-07	criteria provided, single submitter	clinical testing	The NF1 c. c.5269-1G>C variant (rs876660141), also known as c.5206-1G>C for NM_000267.3, is reported in the literature in an individual affected with neurofibromatosis type I (Bonatti 2017). This variant is also reported in ClinVar (Variation ID: 431653). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 37, which is likely to negatively impact gene function. Based on available information, this variant is considered to be likely pathogenic. References: Bonatti F et al. Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I. Int J Mol Sci. 2017 Sep 29;18(10):2071. PMID: 28961165.
GeneDx	RCV001810978	SCV005371724	pathogenic	not provided	2024-04-04	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34328347, 34797032, 28961165)
Ambry Genetics	RCV004992279	SCV005451968	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-07-29	criteria provided, single submitter	clinical testing	The c.5206-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 37 of the NF1 gene. This variant was reported in multiple individuals with features consistent with neurofibromatosis type 1 (NF1) (Muthusamy K et al. Am J Med Genet A, 2022 Mar;188:911-918; Bonatti F et al. Int J Mol Sci, 2017 Sep;18:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497213	SCV005813040	pathogenic	Neurofibromatosis, type 1	2024-03-12	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 36 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with clinical features of neurofibromatosis type I (PMID: 25325900, 28961165, 34328347). ClinVar contains an entry for this variant (Variation ID: 431653). 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	RCV000497213	SCV000588797	likely pathogenic	Neurofibromatosis, type 1	2017-02-02	no assertion criteria provided	clinical testing