Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000523734 | SCV000617913 | uncertain significance | not provided | 2022-04-12 | criteria provided, single submitter | clinical testing | Has been reported as a variant of uncertain significance in an individual with TAAD (Wolford et al., 2019); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 32679894, 31211624, Finsterer2022) |
Ambry Genetics | RCV000618591 | SCV000739800 | uncertain significance | Cardiovascular phenotype | 2014-04-23 | criteria provided, single submitter | clinical testing | The p.N156S variant (also known as c.467A>G), located in coding exon 5 of the FBN1 genein the EGF-like #3 domain, results from an A to G substitution at nucleotide position 467. The asparagine at codon 156 is replaced by serine, an amino acid with highly 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 highly 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. |
Color Diagnostics, |
RCV001185070 | SCV001351211 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2019-06-27 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with serine at codon 156 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Centre for Mendelian Genomics, |
RCV001199083 | SCV001370078 | uncertain significance | Progeroid and marfanoid aspect-lipodystrophy syndrome | 2019-01-09 | criteria provided, single submitter | clinical testing | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. |
Invitae | RCV001220123 | SCV001392097 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-12-25 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 156 of the FBN1 protein (p.Asn156Ser). This variant is present in population databases (rs779490973, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of Marfan syndrome and/or thoracic aortic aneurysm and dissection (PMID: 32679894; Invitae). ClinVar contains an entry for this variant (Variation ID: 449605). 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 expected to disrupt FBN1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Fulgent Genetics, |
RCV002481699 | SCV002791308 | uncertain significance | Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome | 2021-08-13 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000523734 | SCV003833981 | uncertain significance | not provided | 2019-08-28 | criteria provided, single submitter | clinical testing |