Submissions for variant NM_000138.5(FBN1):c.1904A>G (p.Tyr635Cys)

dbSNP: rs1555399816

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623741	SCV000740502	likely pathogenic	Marfan syndrome	2017-06-12	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000623741	SCV000781336	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684933	SCV000812396	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2020-03-06	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 635 of the FBN1 protein (p.Tyr635Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with ectopia lentis (Invitae) and has been reported in other individuals with this condition or Marfan syndrome (PMID: 16222657, 18435798). ClinVar contains an entry for this variant (Variation ID: 520493). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171259	SCV001333967	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-02-20	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000623741	SCV002025520	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS5, PP1, PP4 or PM2, PS5, PP4
Ambry Genetics	RCV001171259	SCV002723706	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-02-07	criteria provided, single submitter	clinical testing	The p.Y635C variant (also known as c.1904A>G), located in coding exon 15 of the FBN1 gene, results from an A to G substitution at nucleotide position 1904. The tyrosine at codon 635 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #06 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 detected in several individuals from cohorts with Marfan syndrome (MFS) or suspected MFS, including individuals with aortic root dilation and ectopia lentis; however, clinical detail was limited in some cases (Arbustini E et al. Hum Mutat, 2005 Nov;26:494; Sakai H et al. Am J Med Genet A, 2006 Aug;140:1719-25; Attanasio M et al. Clin Genet, 2008 Jul;74:39-46; Proost D et al. Hum Mutat, 2015 Aug;36:808-14; Gentilini D et al. PLoS One, 2019 Sep;14:e0222506). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV004702203	SCV005202088	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 520493; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); Introduces a new 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 (PMID: 12938084); This variant is associated with the following publications: (PMID: 34550612, 18435798, 31536524, 35058154, 20591885, 12938084, 16222657)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000623741	SCV005399170	pathogenic	Marfan syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, 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. Missense with both dominant negative and loss of function effects on protein function, are also associated with causing Marfan syndrome and ectopia lentis (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and compounded by variable expressivity (GeneReviews). (I) 0108 - This gene is associated with both recessive and dominant disease. Patients with a recessive form of disease have Marfan syndrome, however there are very few reports (OMIM). (I) 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 (exon 16). (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 a functional calcium-binding EGF-like domain (NCBI). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with both familial ectopia lentis and Marfan syndrome (ClinVar, PMID: 16222657, 16835936, 18435798, 24501682). (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) 1204 - Variant has been shown to be de novo in the proband (parental status not tested but assumed) (VCGS #20G001937, 20G001938). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Center for Medical Genetics Ghent, University of Ghent	RCV000623741	SCV000786809	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing