Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000772653 | SCV000738793 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2020-07-09 | criteria provided, single submitter | clinical testing | The p.R439Q variant (also known as c.1316G>A), located in coding exon 10 of the FBN1 gene, results from a G to A substitution at nucleotide position 1316. The arginine at codon 439 is replaced by glutamine, an amino acid with highly similar properties. Another alteration affecting the same amino acid, p.R439G (c.1315C>G), was reported in a patient with some features of Marfan syndrome (Arbustini E et al. Hum. Mutat., 2005 Nov;26:494). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000772653 | SCV000905912 | likely benign | Familial thoracic aortic aneurysm and aortic dissection | 2020-08-09 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV001002368 | SCV001160276 | uncertain significance | not specified | 2019-02-08 | criteria provided, single submitter | clinical testing | The FBN1 c.1316G>A; p.Arg439Gln variant (rs568810058), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 519712). This variant is found in the Latino population with an overall allele frequency of 0.03% (12/34572 alleles) in the Genome Aggregation Database. The arginine at codon 439 is moderately conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. While another variant at this codon (p.Arg439Gly) has been described in an individual with symptoms of Marfan syndrome, this individual did not fulfill Ghent criteria for diagnosed Marfan syndrome, and the variant was also found in the individual's mother who had no symptoms besides mitral valve prolapse (Arbustini 2005). However, computational predictors (Alamut v.2.11) indicate that the c.1316G>A; p.Arg439Gln variant may impact splicing by creating a novel cryptic splice acceptor site, though RNA analyses would be required to confirm this. Given the lack of clinical and functional data, the significance of the p.Arg439Gln variant is uncertain at this time. References: Arbustini E et al. Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies. Hum Mutat. 2005 Nov;26(5):494. |
| Labcorp Genetics |
RCV001868121 | SCV002165401 | benign | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-01-02 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV003322795 | SCV004028094 | uncertain significance | not provided | 2023-07-05 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein 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: 12938084) |