Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV002313307 | SCV000738981 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2016-09-01 | criteria provided, single submitter | clinical testing | The p.C180Y variant (also known as c.539G>A), located in coding exon 5 of the FBN2 gene, results from a G to A substitution at nucleotide position 539. The cysteine at codon 180 is replaced by tyrosine, an amino acid with highly dissimilar properties. Internal structure analysis reveals that this alteration would result in loss of an EGF-defining disulfide motif and is likely to cause large structural destabilization of the N-terminal domain (Yadin DA et al. Structure, 2013 ;21:1743-56). In one study, 13 of 14 reported FBN2 mutations were found in the middle region of the gene (exons 24-36), and 7 of these mutations were noted to alter or produce a cysteine residue (Callewaert BL et al. Hum Mutat. 2009;30(3):334-341). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Prevention |
RCV003411465 | SCV004107668 | uncertain significance | FBN2-related condition | 2023-06-19 | criteria provided, single submitter | clinical testing | The FBN2 c.539G>A variant is predicted to result in the amino acid substitution p.Cys180Tyr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has been documented as likely pathogenic by a single lab in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/519826/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |