Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001949525 | SCV002243641 | pathogenic | Neurofibromatosis, type 1 | 2021-08-01 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 23913538, 31533651; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 34 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). |
| Ambry Genetics | RCV003170178 | SCV003893772 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-01-13 | criteria provided, single submitter | clinical testing | The c.4662-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 35 in the NF1 gene. This alteration was identified in 1 of 565 unrelated French probands with clinical diagnoses or suspicion of NF1 (Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8).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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Another alteration impacting the same acceptor site (c.4662-2A>G) has been detected in individuals with clinical diagnosis or suspicion of neurofibromatosis type 1 (NF1) (Kang E et al. J Hum Genet, 2020 Jan;65:79-89; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93). 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 a disease-causing mutation. |