Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001002000 | SCV001159815 | pathogenic | not specified | 2018-07-12 | criteria provided, single submitter | clinical testing | The FBN1 c.4816+2T>C variant, to our knowledge, is not described in the medical literature or in gene-specific database. It is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the splice donor site of intron 38 and is predicted to alter splicing (Alamut v.2.11). Additionally, another variant in the donor site of 38 (c.4816+1G>T) has been reported in individuals with Marfan syndrome and is considered pathogenic (Baetens 2011). Based on available information, the c.4816+2T>C variant is considered pathogenic. References: Baetens M et al. Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat. 2011 Sep;32(9):1053-62. |
| Labcorp Genetics |
RCV001071745 | SCV001237065 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2020-12-01 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). Disruption of this splice site has been observed in individuals affected with Marfan syndrome or clinical features of this disease (PMID: 21542060, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 39 of the FBN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Gene |
RCV002225780 | SCV002504595 | pathogenic | not provided | 2022-04-08 | criteria provided, single submitter | clinical testing | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Aberrant splicing is a known mechanism of disease for Marfan syndrome (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19293843, 17657824, 31447099) |
| All of Us Research Program, |
RCV004004469 | SCV004830140 | likely pathogenic | Marfan syndrome | 2023-06-08 | criteria provided, single submitter | clinical testing | This variant causes a T to C nucleotide substitution at the +2 position of intron 39 of the FBN1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual with features of Marfan syndrome, who had three family members also with Marfan syndrome-related features (PMID: 32371921). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants (c.4816+1G>A, c.4816+1G>T) that are predicted to impact the same splice site have been reported in multiple individuals affected with Marfan syndrome (PMID: 21542060, 25907466, 31471346, ClinVar SCV001237065.4). Loss of FBN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. |