Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001054434 | SCV001218747 | uncertain significance | Congenital contractural arachnodactyly | 2023-10-10 | criteria provided, single submitter | clinical testing | This sequence change affects a splice site in intron 15 of the FBN2 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), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in FBN2 cause disease. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of congenital contractural arachnodactyly (Invitae). ClinVar contains an entry for this variant (Variation ID: 850293). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV002416401 | SCV002726626 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2020-10-07 | criteria provided, single submitter | clinical testing | The c.2095+2_2095+7delTAAGTG intronic variant results from a deletion of 6 nucleotides between positions +2 and +7 and involves the canonical splice donor site after coding exon 15 of the FBN2 gene. The canonical splice donor site is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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. However, loss of function of FBN2 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |