Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000631959 | SCV000753062 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2020-02-12 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 65 of the FBN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individuals affected with Marfan syndrome and lipodystrophy (PMID: 24613577). ClinVar contains an entry for this variant (Variation ID: 225629). A different variant affecting this nucleotide (c.8226+1G>T) has been determined to be pathogenic (PMID: 21594993). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Experimental studies have shown that this intronic change causes the skipping of exon 65 during mRNA splicing (PMID: 24613577). This variant does not result in nonsense mediated decay, but creates a truncated protein that lacks the Furin site. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001566353 | SCV001789856 | pathogenic | not provided | 2021-04-30 | criteria provided, single submitter | clinical testing | Published functional studies revealed skipping of exon 65, resulting in a frameshift and creating a premature stop codon, denoted p.His2685Ilefs*9; described as skipping of exon 64 due to alternate nomenclature (Jacquinet et al., 2014); Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as likely pathogenic and pathogenic (ClinVar Variant ID# 225629; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31774634, 27884935, 21594993, 24613577) |
| 3billion | RCV000210934 | SCV002059119 | likely pathogenic | Progeroid and marfanoid aspect-lipodystrophy syndrome | 2022-01-03 | criteria provided, single submitter | clinical testing | The variant has been observed in at least two similarly affected unrelated individuals (PMID: 24613577, 21594993, PS4_M). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10% (PVS1_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000225629).It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| OMIM | RCV000210934 | SCV000267618 | pathogenic | Progeroid and marfanoid aspect-lipodystrophy syndrome | 2019-02-28 | no assertion criteria provided | literature only | |
| Center for Medical Genetics Ghent, |
RCV000664017 | SCV000787405 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |