Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000663936 | SCV003762192 | pathogenic | Marfan syndrome | 2022-12-01 | reviewed by expert panel | curation | The NM_000138 c.7204+1G>T variant in FBN1 is a splice site variant predicted to affect a donor splice site in intron 57 of the gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with aortic root dilatation and a systemic score of 7 or above which is a highly specific phenotype for Marfan syndrome (PP4). The variant segregates with the disease in 4 family members (PP1_moderate). This variant has been reported 2 times in ClinVar as pathogenic/ likely pathogenic (Variation ID: 549394). At least 3 other probands with Marfan syndrome carry an alternative nucleotide change at this position (PMID: 30101859, PMID: 29357934, PMID: 19293843). This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). This variant was identified as de novo in one patient (PM6; Invitae data in ClinVar). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PP1_moderate, PM6, PM2_supporting, PP4 |
| Invitae | RCV001381120 | SCV001579372 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2020-11-02 | criteria provided, single submitter | clinical testing | 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). 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 clinical features of Marfan syndrome (PMID: 29357934, 30101859, 19293843). ClinVar contains an entry for this variant (Variation ID: 549394). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 58 of the FBN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Centre of Medical Genetics, |
RCV000663936 | SCV002025438 | likely pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PS7, PP4 |
| Center for Medical Genetics Ghent, |
RCV000663936 | SCV000787311 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |