ClinVar Genomic variation as it relates to human health

This missense variant replaces arginine with cysteine at codon 332 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with non-syndromic aortic dissection (PMID: 28973303) and in another individual affected with isolated thoracic aortic aneurysm and dissection (PMID: 33824467). This variant has been identified in 1/251234 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.R332C variant (also known as c.994C>T), located in coding exon 9 of the FBN1 gene, results from a C to T substitution at nucleotide position 994. The arginine at codon 332 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the TGFBP #01 domain. 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 has been reported in an individual with sporadic, non-syndromic subclavian aortic dissection (Tan L et al. Hum Mol Genet, 2017 12;26:4814-4822). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

PP2, PP3, PM1, PM2, PS4_moderate

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 332 of the FBN1 protein (p.Arg332Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 28973303, 33824467; internal data). ClinVar contains an entry for this variant (Variation ID: 982352). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

The FBN1 c.994C>T; p.Arg332Cys variant (rs1161109360) is reported in the literature in individuals affected with thoracic aortic aneurysms and dissections (Li 2021, Tan 2017, Zhu 2021). This variant is also reported in ClinVar (Variation ID: 982352). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. The arginine at codon 332 is located closely between a calcium binding EGF-like domain and TB domain. The disulfide bridges formed between conserved cysteine residues within these domains are essential for protein folding; creation of a new cysteine may interfere with proper disulfide bridge formation, disrupting protein structure (Yuan 1997). Accordingly, the revised Ghent nosology for Marfan syndrome lists missense variants creating or affecting cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). However, the effect of this variant has not been characterized by functional studies. Computational analyses predict that this variant is deleterious (REVEL: 0.823). Based on available information, this variant is considered to be likely pathogenic. References: Li Y et al. Evaluating the monogenic contribution and genotype-phenotype correlation in patients with isolated thoracic aortic aneurysm. Eur J Hum Genet. 2021 Jul;29(7):1129-1138. PMID: 33824467. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. PMID: 20591885. Tan L et al. FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection. Hum Mol Genet. 2017 Dec 15;26(24):4814-4822. PMID: 28973303. Yuan X et al. Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils. EMBO J. 1997 Nov 17;16(22):6659-66. PMID: 9362480. Zhu G et al. Novel LTBP3 mutations associated with thoracic aortic aneurysms and dissections. Orphanet J Rare Dis. 2021 Dec 14;16(1):513. PMID: 34906192.

FBN1: PM2, PS4:Moderate