Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000197515 | SCV000250179 | uncertain significance | not provided | 2018-07-13 | criteria provided, single submitter | clinical testing | p.Lys1019Asn (AAG>AAC): c.3057 G>C in exon 24 of the FBN2 gene (NM_001999.3) The K1019N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K1019N variant was not observed in approximately 6,500 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 K1019N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is class conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported, indicating 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 TAADV2-1 |
| Invitae | RCV001853144 | SCV002137832 | uncertain significance | Congenital contractural arachnodactyly | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1019 of the FBN2 protein (p.Lys1019Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213296). 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 not expected to disrupt FBN2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002444791 | SCV002753591 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2020-11-23 | criteria provided, single submitter | clinical testing | The p.K1019N variant (also known as c.3057G>C), located in coding exon 24 of the FBN2 gene, results from a G to C substitution at nucleotide position 3057. The lysine at codon 1019 is replaced by asparagine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |