Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000460069 | SCV000542016 | pathogenic | Neurofibromatosis, type 1 | 2021-06-17 | 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, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 23668869). ClinVar contains an entry for this variant (Variation ID: 404449). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 44 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 | RCV004559060 | SCV005048683 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-09-20 | criteria provided, single submitter | clinical testing | The c.6757-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 45 of the NF1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript 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 altered amino acid sequence is unknown; however, and the impacted region is critical for protein function (Ambry internal data). Another alteration impacting the same acceptor site (c.6757-2A>C) has been detected in two individuals with clinical diagnosis of neurofibromatosis type 1 (Pasmant E et al. Eur. J. Hum. Genet., 2015 May;23:596-601; Hutter S et al. Hum. Genet., 2016 May;135:469-75). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |