Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000199274 | SCV000250214 | uncertain significance | not specified | 2017-01-05 | criteria provided, single submitter | clinical testing | The V1548I variant of uncertain significance in the FBN2 gene has not been published as a pathogenic variant or beenreported as a benign variant to our knowledge. This variant has been identified in multiple unrelated individualsreferred for Marfan/TAAD genetic testing at GeneDx, although segregation data from these individuals is not sufficientto determine the pathogenicity of this variant. While it was not observed with any significant frequency in individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, the 1000 Genomes Project andthe Exome Aggregation Consortium report that the V1548I variant was observed in approximately 0.1% of allelesfrom individuals of South Asian background, indicating it may be a rare benign variant in this population. Thissubstitution occurs at a position that is conserved by class; however, I1548 is tolerated in at least one species. TheV1548I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. Consequently, in silico analysis is inconsistent in its predictions as to whetheror not the variant is damaging to the protein structure/function. Finally, the V1548I variant does not affect a Cysteineresidue within a calcium-binding EGF-like domain of the FBN2 gene. Cysteine substitutions in the calcium-bindingEGF-like domains represent the majority of pathogenic missense changes associated with congenital arachnodactyly(Collod-Beroud et al., 2003; Frédéric et al., 2009).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. |
| Ambry Genetics | RCV002315584 | SCV000738954 | likely benign | Familial thoracic aortic aneurysm and aortic dissection | 2020-11-30 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Invitae | RCV000863851 | SCV001004573 | likely benign | Congenital contractural arachnodactyly | 2024-01-19 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV000863851 | SCV001314068 | likely benign | Congenital contractural arachnodactyly | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. |
| Genome Diagnostics Laboratory, |
RCV002277528 | SCV002567196 | uncertain significance | Connective tissue disorder | 2019-03-01 | criteria provided, single submitter | clinical testing |