Submissions for variant NM_001042492.3(NF1):c.3114-1G>A

dbSNP: rs1555614611

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660026	SCV000781972	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000660026	SCV001384650	likely pathogenic	Neurofibromatosis, type 1	2019-10-07	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 23 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 547621). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000660026	SCV001478947	likely pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000660026	SCV002559931	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002325332	SCV002607904	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-08-11	criteria provided, single submitter	clinical testing	The c.3114-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 24 of the NF1 gene. One of the resulting transcripts is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data). In addition, another alteration impacting the same acceptor site (c.3114-2A>G) has been described in an individual with suspected diagnosis of neurofibromatosis type I (Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60). c.3114-1G>A was not reported in population-based 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 will result in the creation or strengthening of a novel splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.