Submissions for variant NM_000138.5(FBN1):c.5999G>A (p.Cys2000Tyr)

dbSNP: rs1555395645

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004025276	SCV000742446	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-01-17	criteria provided, single submitter	clinical testing	The p.C2000Y pathogenic mutation (also known as c.5999G>A), located in coding exon 48 of the FBN1 gene, results from a G to A substitution at nucleotide position 5999. The cysteine at codon 2000 is replaced by tyrosine, an amino acid with highly dissimilar properties. 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 determined to be the result of a de novo mutation or germline mosaicism in one individual with features consistent with Marfan syndrome (Ambry internal data). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the cbEGF30 domain (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002532843	SCV003230281	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-08-20	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 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: 521729). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2000 of the FBN1 protein (p.Cys2000Tyr).
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	RCV004764793	SCV005374706	likely pathogenic	Marfan syndrome	2024-02-08	criteria provided, single submitter	clinical testing	PM1_Str PM2_Supp PM6_Supp PP2_Supp PP3_Supp