Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000254043 | SCV000319126 | uncertain significance | Cardiovascular phenotype | 2013-09-18 | criteria provided, single submitter | clinical testing | The p.N1499H variant (also known as c.4495A>C) is located in coding exon 35 of the FBN2 gene. This alteration results from an A to C substitution at nucleotide position 4495. The asparagine at codon 1499 is replaced by histidine, an amino acid with some similar properties. 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. Based on protein sequence alignment, this amino acid position is 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 variant remains unclear. |
Gene |
RCV001552142 | SCV001772786 | uncertain significance | not provided | 2023-07-11 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (Callewaert et al., 2008; Frederic et al., 2009); This variant is associated with the following publications: (PMID: 19006240, 18767143) |
Invitae | RCV003525891 | SCV004284142 | uncertain significance | Congenital contractural arachnodactyly | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1499 of the FBN2 protein (p.Asn1499His). This variant is present in population databases (rs771260299, gnomAD 0.002%). 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: 263771). 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. 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. |