Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420801 | SCV001623169 | uncertain significance | not specified | 2021-05-17 | criteria provided, single submitter | clinical testing | Variant summary: FBN1 c.7409G>T (p.Cys2470Phe) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251366 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7409G>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Missense mutations affecting or creating cysteine residues are listed among the criteria for a causal FBN1 mutation when identified as de novo (with proven paternity) in the revised Ghent criteria for the diagnosis of Marfan and related conditions (Loeys 2010). Based on the evidence outlined above, until the de novo origin of this variant is unequivocally confirmed, the variant is classified as VUS-possibly pathogenic. |
| Kariminejad - |
RCV001814319 | SCV001755426 | likely pathogenic | Abnormality of connective tissue | 2021-07-10 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001859335 | SCV002228703 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2021-11-05 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys2470 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 17657824, 23653584; Invitae), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 1098776). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 2470 of the FBN1 protein (p.Cys2470Phe). |