Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000200193 | SCV000250295 | uncertain significance | not provided | 2015-05-28 | criteria provided, single submitter | clinical testing | p.His1514Tyr (H1514Y) (CAT>TAT): c.4540 C>T in exon 35 of the FBN2 gene (NM_001999.3) The H1514Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H1514Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H1514Y variant is 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. This substitution occurs at a position where amino acids with similar properties to tyrosine are tolerated across species. While this variant is located in the calcium-binding EGF-like domain 25, it does not affect a Cysteine residue within this domain. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with CCA (Collod-Beroud et al.,2003). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Futhermore, no missense mutations in nearby residues have been reported, suggesting this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-PANCARD |