Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001055827 | SCV001220237 | pathogenic | Neurofibromatosis, type 1 | 2022-12-23 | 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. ClinVar contains an entry for this variant (Variation ID: 851432). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 22222937; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 40 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 | RCV002355044 | SCV002656256 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-02-15 | criteria provided, single submitter | clinical testing | The c.6084+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 40 of the NF1 gene. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with NF1-related disease (Bianco G et al. Neurol Sci, 2012 Dec;33:1483-5, Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor 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. Another alteration impacting the same donor site (c.6084+1G>A) has also been described in individuals with personal and/or family history that is consistent with NF1-related disease (De Luca A, et al. Hum. Mutat. 2004;23(6):629; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |