Submissions for variant NM_000138.5(FBN1):c.433T>C (p.Cys145Arg)

dbSNP: rs1555405031

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550317	SCV000627914	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-02-10	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Marfan syndrome (PMID: 21895641; Invitae). 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 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). 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: 457211). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 145 of the FBN1 protein (p.Cys145Arg).
Ambry Genetics	RCV002314922	SCV000738826	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-05-03	criteria provided, single submitter	clinical testing	The p.C145R variant (also known as c.433T>C), located in coding exon 4 of the FBN1 gene, results from a T to C substitution at nucleotide position 433. The cysteine at codon 145 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the EGF-like #02 domain. This variant was detected in a cohort of individuals reported to have symptoms of Marfan syndrome; however, clinical details were not provided (Robinson DO et al. Clin Genet. 2012;82:223-31). Another alteration affecting the same amino acid, p.C145Y (c.434G>A), was reported in a proband and a clinically affected relative from a cohort of patients with Marfan syndrome or Marfan-like phenotype (Howarth R et al. Genet Test. 2007;11:146-52). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Internal structural assessment indicates this alteration results in loss of a structural disulfide in EGF domain 2 (Yadin DA. Structure. 2013;21(10):1743-56). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide in the structurally sensitive EGF-like domain #02. 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 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.