Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000989783 | SCV001140342 | pathogenic | Neurofibromatosis, type 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002337048 | SCV002635062 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-03-28 | criteria provided, single submitter | clinical testing | The c.1186-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 11 of the NF1 gene. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the altered amino acid sequence is unknown; however, several alterations impacting this acceptor site have been identified in individuals with clinical diagnoses of neurofibromatosis type 1 and have been shown to have a similar impact on splicing (Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Brekelmans C et al. Hum. Mutat., 2019 10;40:1760-1767; Melloni G et al. Cancers (Basel), 2019 11;11). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV000989783 | SCV004452128 | pathogenic | Neurofibromatosis, type 1 | 2023-04-04 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 31766501, 33443663; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 10 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 5 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. ClinVar contains an entry for this variant (Variation ID: 803341). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in 10 (PMID: 31766501). |