ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6503A>G (p.Asp2168Gly) (rs1555395015)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523160 SCV000617602 likely pathogenic not provided 2017-03-20 criteria provided, single submitter clinical testing The D2168G likely pathogenic variant in the FBN1 gene has been previously reported in one individual with suspected Marfan syndrome (Howarth et al., 2007). Although one of the two family members also found to carry D2168G was unaffected, no additional clinical information was provided. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D2168G variant results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, this substitution affects an aspartic acid residue within the consensus sequence of a calcium-binding EGF-like domain at a position that is occupied exclusively by either aspartic acid (Asp) or asparagine (Asn). Substitution of conserved residues within the consensus sequence is a recognized mechanism of disease and is included in the criteria to consider for pathogenicity in the revised Ghent nosology (Loeys et al., 2010). Finally, D2168 is conserved across mammals. In summary, D2168G in the FBN1 gene is interpreted as a likely pathogenic variant.
Invitae RCV000531397 SCV000627965 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 2168 of the FBN1 protein (p.Asp2168Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals with suspected Marfan syndrome (PMID: 17627385, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on FBN1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.