Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590660 | SCV000695508 | uncertain significance | not provided | 2016-01-27 | criteria provided, single submitter | clinical testing | Variant summary: The c.3379G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. This variant is not found in 121560 control chromosomes. Francke U. et al (1995) described the association of this variant with ascending aortic disease based on the presence of this variant in multiple affected individuals from one family presented with various cardiac defects. None of these patients presented with classical MFS. Phenotypes varied from aneurysm, dissection of the ascending aorta to mild aortic root dilation. Nine affected individuals were heterozygous for the variant however one affected family member did not carry the variant of interest. While the combined clinical data on this family suggest the presence of a systemic connective-tissue disorder that overlaps with MFS, other genes associated with TAAD, such as ACTA2, TGFBR1, TGFBR2 and MYH11 have not been screened for mutations. This variant has been identified in at least 2 family members with isolated major cardiac features referred for genetic testing. None of these individuals presented with major/minor skeletal features suggestive of MFS (internal LCA data). Functional studies performed on fibroblasts from c.3379G>A carrier revealed decreased fibrillin deposition into the extracellular matrix. Taken together, this variant was classified as VUS-possibly pathogenic. |
| Invitae | RCV000631963 | SCV000753066 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2020-03-25 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change disrupts localized fibrillin folding, which does not significantly impact synthesis and trafficking, but reduces fibrillin deposition into the extracellular matrix, suggesting an extracellular dominant negative effect (PMID: 7762551, 952872, 12651868). This glycine residue is located in a FBN1 calcium-binding epidermal growth factor (cbEGF)-like domain in a position that is predicted to affect protein structure and function (PMID: 19802897). In addition, missense variants at this position of the cbEGF-like domain are overrepresented among individuals with Marfan syndrome (PMID: 12938084). This variant has been reported to segregate with ascending aortic dilatation, aneurysm, and dissection in a single family (PMID: 7762551). ClinVar contains an entry for this variant (Variation ID: 16443). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 1127 of the FBN1 protein (p.Gly1127Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. |
| OMIM | RCV000017905 | SCV000038184 | pathogenic | Marfan syndrome, mild | 1995-06-01 | no assertion criteria provided | literature only |