Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780246 | SCV000917354 | uncertain significance | not specified | 2017-10-24 | criteria provided, single submitter | clinical testing | Variant summary: The FBN1 c.4057G>T (p.Gly1353Trp) variant located in the cb EGF-like #18 domain (via UMD) involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant is absent in 246104 control chromosomes (gnomAD). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. However, another variant affecting the same codon, c.4057G>A (p.Gly1353Arg) has been reported in at least one affected individual suggesting the codon could be important for proper FBN1 function, although Cysteines have been well-established to play a key role in FBN1 protein function. Therefore, due to lack of clinical information and/or functional studies, the variant is classified as a "Variant of Uncertain Significance - Possibly Pathogenic," until additional information becomes available. |
| Labcorp Genetics |
RCV001295623 | SCV001484558 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-03-04 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 1353 of the FBN1 protein (p.Gly1353Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 632808). 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 with a positive predictive value of 95%. This variant disrupts the p.Gly1353 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19293843, 31211624; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Ambry Genetics | RCV002325482 | SCV002632429 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2018-11-29 | criteria provided, single submitter | clinical testing | The p.G1353W variant (also known as c.4057G>T), located in coding exon 32 of the FBN1 gene, results from a G to T substitution at nucleotide position 4057. The glycine at codon 1353 is replaced by tryptophan, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #18 domain. Another variant affecting this codon (p.G1353R, c.4057G>A) was detected in an individual from a suspected Marfan syndrome cohort, who did not meet Ghent criteria and also had a second variant in FBN1 (Stheneur C et al. Eur. J. Hum. Genet. 2009 Sep;17:1121-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |