Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002319345 | SCV001184096 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2018-02-02 | criteria provided, single submitter | clinical testing | The c.4367+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 32 of the NF1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 | RCV002550875 | SCV003274498 | pathogenic | Neurofibromatosis, type 1 | 2023-09-18 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 29952103). This sequence change affects a donor splice site in intron 32 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 12807981, 25325900, 29952103; Invitae). ClinVar contains an entry for this variant (Variation ID: 824831). |