Submissions for variant NM_000138.5(FBN1):c.2237A>G (p.Tyr746Cys)

dbSNP: rs1555399372

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590010	SCV000695482	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2017-02-08	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.2237A>G (p.Tyr746Cys) variant involves the alteration of a conserved nucleotide and results in a replacement of a large size and aromatic Tyrosine (Y) with a medium size and polar Cysteine (C) located in a Ca-binding EGF-like domain (Giampietro_COP_2002). 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in the ExAC database (0/121350 control chromosomes), a large control database. A patient harboring the variant displayed a classic Marfan syndrome phenotype that involved "the ocular, skeletal, and cardiovascular systems" (Nijbroek_AJHG_1995). Family studies showed that the variant was a sporadic, de novo mutational event. Taken together and given that a cysteine is gained which is a frequent mechanism of disease, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058020	SCV001222555	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2020-01-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed to be de novo in an individual affected with Marfan syndrome (PMID: 7611299). ClinVar contains an entry for this variant (Variation ID: 495574). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 746 of the FBN1 protein (p.Tyr746Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine.
Centre of Medical Genetics, University of Antwerp	RCV002245999	SCV002025530	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS5, PP4
GeneDx	RCV002286762	SCV002577259	likely pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	Has been reported in an individual with Marfan syndrome (Nijbroek et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 9401003, 7611299)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224806	SCV003920881	likely pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-03-30	criteria provided, single submitter	clinical testing	FBN1 NM_000138.4 exon 18 p.Tyr746Cys (c.2237A>G): This variant has been reported in the literature as a de novo variant in one individual with classic Marfan syndrome (Nijbroek 1995 PMID:7611299). This variant is not present in large control databases but is present in ClinVar (Variation ID:495574). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant is predicted to affect a cysteine residue. Cysteine in the FBN1 gene is reported to have important functional relevance; variants that involve a cysteine residue are reported to be particularly significant (Dietz 1992 PMID:1301946). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV002245999	SCV004048005	likely pathogenic	Marfan syndrome		criteria provided, single submitter	clinical testing	The missense c.2237A>G (p.Tyr746Cys) variant in FBN1 gene has been reported in heterozygous state in association with Marfan syndrome; there Family studies showed that the variant was a sporadic, de novo mutational event. (Nijbroek G et al., 1995).The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Tyr at position 746 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr746Cys in FBN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Also, cysteine is gained, which is a frequent mechanism of disease. For these reasons, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV002286762	SCV004704328	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	FBN1: PM1:Strong, PM2, PS4:Moderate, PM6:Supporting, PP4