Submissions for variant NM_000138.5(FBN1):c.2050T>C (p.Cys684Arg)

dbSNP: rs1555399764

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002314307	SCV000738777	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2016-03-31	criteria provided, single submitter	clinical testing	The p.C684R variant (also known as c.2050T>C), located in coding exon 16 of the FBN1 gene, results from a T to C substitution at nucleotide position 2050. The cysteine at codon 684 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the TGFBP #02 domain. This alteration was reported as de novo in a subject reported to have classical Marfan syndrome (Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8). The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860397	SCV002243927	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-03-05	criteria provided, single submitter	clinical testing	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. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 519705). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 684 of the FBN1 protein (p.Cys684Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 19293843). In at least one individual the variant was observed to be de novo.
GeneDx	RCV004701708	SCV005202087	pathogenic	not provided	2023-11-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a cysteine residue within a TGF-binding protein domain (aka TB domain or 8-Cysteine domain) and is expected to disrupt disulfide bonding within this domain; other missense substitutions that affect cysteine residues within this TGF-binding protein domain have been reported in association with various FBN1-related phenotypes, including Marfan syndrome (HGMD); This variant is associated with the following publications: (PMID: 19293843)
Center for Medical Genetics Ghent, University of Ghent	RCV000663513	SCV000786820	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing