Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV002319363 | SCV001184649 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2018-01-09 | criteria provided, single submitter | clinical testing | The c.4661+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 34 in the NF1 gene. This nucleotide position is highly conserved in available vertebrate species. The BDGP splice site prediction tool predicts that this alteration will abolish the native splice donor site. Using the Human Splicing Finder (HSF) splice site prediction tool, this alteration is predicted to significantly weaken the native splice donor site; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). 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 likely pathogenic. |
Invitae | RCV001862233 | SCV002230644 | pathogenic | Neurofibromatosis, type 1 | 2021-09-09 | 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: 825080). Disruption of this splice site has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 19449407; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor 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). |
Genome- |
RCV001862233 | SCV002560082 | pathogenic | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing |