Submissions for variant NM_000138.5(FBN1):c.1556A>G (p.Tyr519Cys)

dbSNP: rs1555400278

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663468	SCV004123041	pathogenic	Marfan syndrome	2023-11-16	reviewed by expert panel	curation	The NM_00138 c.1556A>G, is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 519 (p.Tyr519Cys). This variant was found in at least 7 probands with features consistent with or suggestive of Marfan syndrome including the following: one proband who met the original Ghent criteria with cardiovascular, skeletal, and skin involvement; one proband with bilateral ectopia lentis (EL) and systemic features; one proband with thoracic aortic aneurysm and dissection (TAAD); one proband with EL and systemic features; one proband with isolated EL; one proband with TAAD and systemic features; and once as de novo with confirmed maternity/paternity with bilateral EL, TAAD, and systemic features, a phenotype highly specific for Marfan syndrome (PS2_supporting, PS4; PMID: 15241795; University of Tokyo, UZG, Invitae, & Ambry internal data; ClinVar Variation ID: 5490254). The variant also segregates with features of Marfan syndrome in at least two affected family members (PP1; Invitae internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein’s structure or function (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1, PS2_supporting, PM2_supporting, PP1, PP2, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695446	SCV000823945	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-02-17	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 519 of the FBN1 protein (p.Tyr519Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 15241795; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 549024). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000663468	SCV002557320	pathogenic	Marfan syndrome	2022-03-31	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 FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (GeneReviews). (I) 0107 - This gene is predominantly associated with autosomal dominant disease while autosomal recessive forms of Marfan syndrome have been infrequently reported (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (GeneReviews, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (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 and moderately conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional EGF domain. Additionally, the variant affects a critical residue within the EGF core (PMID: 31227806). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in three individuals with Marfan syndrome and/or aortic dilatation, including one de novo individual (PMID: 15241795; Invitae - personal communication). It should also be noted that this variant has been classified as a VUS by another clinical diagnostic laboratory; however, no justification was provided for their classification (ClinVar). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in the proband’s family. (SP) 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
Institute of Human Genetics, University Hospital Muenster	RCV000663468	SCV002577970	uncertain significance	Marfan syndrome	2022-02-16	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PP3,BP1
Ambry Genetics	RCV002397346	SCV002705577	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-12-19	criteria provided, single submitter	clinical testing	The p.Y519C variant (also known as c.1556A>G), located in coding exon 12 of the FBN1 gene, results from an A to G substitution at nucleotide position 1556. The tyrosine at codon 519 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #03 domain. In one study, this variant was detected in an individual reported to have Marfan syndrome (Loeys B et al. Hum. Mutat. 2004 Aug;24(2):140-6). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000663468	SCV000786764	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing