Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000690736 | SCV000818436 | uncertain significance | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2019-02-01 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with FBN1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within 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 disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 807 of the FBN1 protein (p.Asp807Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant also falls at the last nucleotide of exon 20 of the FBN1 coding sequence, which is part of the consensus splice site for this exon. |
| Center for Genomics, |
RCV002060872 | SCV002495767 | 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 | 2021-10-26 | criteria provided, single submitter | clinical testing | FBN1 NM_000138.4 exon 20 p.Asp807Asn (c.2419G>A): This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID:569969). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. This variant alters the last nucleotide in the exon, and splice prediction tools suggest that this variant may affect splicing. However, further studes are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. |