Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181570 | SCV000233873 | likely pathogenic | not provided | 2022-11-14 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Variant in the last nucleotide of the exon in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 35058154, 20591885, Yang2022[CaseReport], 19293843, 21542060) |
| Centre of Medical Genetics, |
RCV000663875 | SCV002025397 | likely pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PS6, PP4 |
| Ambry Genetics | RCV003352796 | SCV004078997 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-08-14 | criteria provided, single submitter | clinical testing | The c.6496G>A variant (also known as p.D2166N), located in coding exon 52 of the FBN1 gene, results from a G to A substitution at nucleotide position 6496. The aspartic acid at codon 2166 asparagine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 52, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in individuals reported to have Marfan syndrome; however, in some cases, clinical details were limited and reported patients may overlap (Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Baetens M et al. Hum Mutat, 2011 Sep;32:1053-62; Meester JAN et al. Genet Med, 2022 May;24:1045-1053; Proost D et al. Hum Mutat, 2015 Aug;36:808-14). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. In addition, as a missense substitution this 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. |
| Labcorp Genetics |
RCV003765116 | SCV004570900 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-07-07 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2166 of the FBN1 protein (p.Asp2166Asn). This variant also falls at the last nucleotide of exon 53, which is part of the consensus splice site for this exon. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 200087). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 19293843, 21542060; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). |
| Center for Medical Genetics Ghent, |
RCV000663875 | SCV000787239 | uncertain significance | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |