Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002314300 | SCV000738765 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2016-02-01 | criteria provided, single submitter | clinical testing | The p.I2185T variant (also known as c.6554T>C), located in coding exon 53 of the FBN1 gene, results from a T to C substitution at nucleotide position 6554. The isoleucine at codon 2185 is replaced by threonine, an amino acid with similar properties. This variant was observed in a Marfan syndrome cohort in which patients were described to have fulfilled revised Ghent nosology; however, clinical details were not provided (Baetens M et al. Hum. Mutat. 2011;32(9):1053-62; Aalberts JJ et al. Gene. 2014;534(1):40-3). In another study, this variant was observed in a patient with minor involvement of the skeletal system and major involvement of the cardiovascular system indicating revised Ghent nosology for a diagnosis of Marfan syndrome was not fulfilled (Comeglio P et al. Hum. Mutat. 2007;28(9):928). 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. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000812728 | SCV000953051 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-09-10 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 17657824, 21542060, 24161884, 31211626; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2185 of the FBN1 protein (p.Ile2185Thr). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 519696). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. |
| Centre of Medical Genetics, |
RCV000663877 | SCV002025399 | likely pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PS1, PP4 |
| Center for Medical Genetics Ghent, |
RCV000663877 | SCV000787241 | uncertain significance | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |