Submissions for variant NM_001042492.3(NF1):c.288+5G>A

dbSNP: rs1555605409

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796289	SCV000935795	pathogenic	Neurofibromatosis, type 1	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with neurofibromatosis type 1 (PMID: 27999334, 29618358; internal data). ClinVar contains an entry for this variant (Variation ID: 642764). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.288+5G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12624144, 22617876). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000796289	SCV001429400	likely pathogenic	Neurofibromatosis, type 1	2019-01-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000796289	SCV002561568	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002462147	SCV002756823	likely pathogenic	not provided	2022-05-17	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22617876, 17576681, 12624144, 9536098, 31766501, 29618358, 27999334, 31776437)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002462147	SCV002774839	likely pathogenic	not provided	2021-07-28	criteria provided, single submitter	clinical testing	This variant has been reported in individuals with Neurofibromatosis type 1 (NF1) in the published literature (PMIDs: 27999334 (2016) and 29618358 (2018)). A different variant located at the same nucleotide position (NF1 c.288+5G>C) has been shown to result in aberrant NF1 splicing and exon 3 skipping and reported to be deleterious (PMID: 12624144 (2003), 22617876 (20012), ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/)). Therefore, the variant is classified as likely pathogenic.
Ambry Genetics	RCV004559662	SCV005047635	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-09-21	criteria provided, single submitter	clinical testing	The c.288+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 3 in the NF1 gene. This alteration was identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Cunha KS et al. Genes (Basel), 2016 Dec;7:; Corsello G et al. Ital J Pediatr, 2018 Apr;44:45). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.