ClinVar Genomic variation as it relates to human health

The Cys1408Arg variant in FBN1 has been previously reported in 4 individuals wit h clinical features of Marfan syndrome, segregated with disease in 5 affected fa mily members from 1 family including 2 obligate carriers, and was absent from la rge population studies (Stheneur 2009, Yoo 2010, LMM unpublished data). The cyst eine (Cys) at position 1408 is highly conserved in mammals and evolutionarily di stant species, supporting that a change at this position may not be tolerated. I n addition, this variant affects a cysteine residue; cysteine substitutions are a common finding in individuals with Marfan syndrome (Schrijver, 1999). In summa ry, this variant meets our criteria to be classified as pathogenic based on the available evidence described above (http://pcpgm.partners.org/LMM).

For these reasons, this variant has been classified as 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: 42351). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1408 of the FBN1 protein (p.Cys1408Arg). 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, 19863550). In at least one individual the variant was observed to be de novo.

Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; 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).; Reported in ClinVar as pathogenic and reported by one external lab to segregate with disease in multiple affected relatives from one family (ClinVar Variant ID# 42351; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31536524, 19293843, 19863550, 24793577, 31730815)

PM2, PVS2, PP4

The p.C1408R pathogenic mutation (also known as c.4222T>C), located in coding exon 34 of the FBN1 gene, results from a T to C substitution at nucleotide position 4222. The cysteine at codon 1408 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in association with Marfan syndrome and thoracic aortic aneurysm and dissection (TAAD) (Tan L et al. Hum Mol Genet, 2017 12;26:4814-4822; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Baetens M et al. Hum Mutat, 2011 Sep;32:1053-62; Lerner-Ellis JP et al. Mol Genet Metab, 2014 Jun;112:171-6; Gentilini D et al. PLoS One, 2019 Sep;14:e0222506; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, other alterations affecting the same amino acid, p.C1408F (c.4223G>T) and p.C1408S (c.4223G>C), have been reported in association with FBN1-related disease (Tiecke F et al. Eur J Hum Genet, 2001 Jan;9:13-21; Tan L et al. Hum Mol Genet, 2017 12;26:4814-4822). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive EGF/cbEGF domain #20. 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

Variant interpreted as Pathogenic and reported on 05-02-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.