Submissions for variant NM_000138.5(FBN1):c.1753G>A (p.Gly585Arg)

dbSNP: rs1085307528

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490226	SCV000576648	uncertain significance	not provided	2017-04-24	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FBN1 gene. The G585R variant, arising from the c.1753 G>A nucleotide substitution, has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G585R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. The same G585R missense variant arising from a different nucleotide substitution in the FBN1 gene, c.1753 G>C, has been reported in one individual diagnosed with incomplete Marfan syndrome who had a family history suggestive of Marfan syndrome (Khau Van Kien et al., 2010). Additionally, a different missense variant at the same residue in the FBN1 gene (G585E) has been reported in association with Marfan syndrome (Baumgartner et al., 2005). However, no segregation data were reported for either the c.1753 G>C (G585R) or G585E variants, and the clinical significance of these variants remain to be definitively determined. Moreover, G585R does not affect a Cysteine residue within a calcium-binding (cb) EGF-like domain of the FBN1 gene, which is the most common mechanism of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377294	SCV001574582	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-03	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Gly585 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 426255). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 19802897; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 585 of the FBN1 protein (p.Gly585Arg).