Submissions for variant NM_000138.5(FBN1):c.7712G>A (p.Cys2571Tyr)

dbSNP: rs1555394153

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269524	SCV001449569	likely pathogenic	not provided	2014-09-24	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000663970	SCV001976992	pathogenic	Marfan syndrome	2021-10-01	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP2, PP3, PP4, PP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000663970	SCV002767884	pathogenic	Marfan syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Marfan syndrome (MIM#154700). Loss of function can be caused by variants that result in premature termination codons and missense variants, whereas dominant negative are most commonly associated with missense variants (PMID: 28596305). The exact genotype-phenotype correlation for this gene is still unclear. However, patients with premature termination variants frequently presented with more systemic features of Marfan syndrome and most also suffered aortic event. Marfan syndrome patients with missense variants presented a higher prevalence of ectopia lentis. (PMID: 29357934) (I) 0107 - This gene is associated with autosomal dominant disease. Patients with an autosomal recessive form of Marfan syndrome have also been reported but are very rare (OMIM, PMID: 30485715). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants in this gene are associated with several allelic disorders, and different phenotypes have been associated with the same variants (OMIM, PMID: 20301510). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional calcium-binding EGF-like 45 domain (PDB). Missense variants impacting a cysteine residue in a calcium-binding EGF-like domain in the FBN1 protein are likely to impact protein function (PMID: 31227806). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The p.Cys2571Arg, p.Cys2571Phe and p.Cys2571Trp variants have been reported in patients with Marfan syndrome (ClinVar, PMIDs: 16222657, 26133393, 30293248). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in patients with Marfan syndrome with or without ectopia lentis (ClinVar, PMIDs: 27724990, 28588436). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000663970	SCV004848462	likely pathogenic	Marfan syndrome	2020-08-24	criteria provided, single submitter	clinical testing	The p.Cys2571Tyr variant in FBN1 has been identified in 2 individuals with Marfan syndrome and was identified as a germline mosaic variant in an unafffected parent (Zhurayev 2016 PubMed: 27724990; Martínez-Quintana 2017 PubMed: 28588436). This variant was absent from large population studies and is reported in ClinVar (allele ID: 539523). Three additional variants involving this codon (p.Cys2571Arg, p.Cys2571Trp and p.Cys2571Phe) have been identified in individuals with Marfan syndrome (Arbustini 2005 PMID: 16222657; Yang 2016 PMID: 27611364; Nair 2018 PMID: 30293248). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant affects a highly conserved cysteine residue in the EGF-like domains, which is a common finding in individuals with Marfan syndrome (Schrijver 1999). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM1; PM2; PM5; PP3; PS4_Supporting.
Center for Medical Genetics Ghent, University of Ghent	RCV000663970	SCV000787350	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing