Submissions for variant NM_000138.5(FBN1):c.7916A>G (p.Tyr2639Cys)

gnomAD frequency: 0.00001  dbSNP: rs794728280

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181620	SCV000233923	pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	Has been identified in individuals with Marfan syndrome or FBN1-related disorders referred for genetic testing at GeneDx, and in published literature (Matyas et al., 2002; Voermans et al., 2009; Attanasio et al., 2013); 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: 19659760, 23684891, 11933199, 27146836, 20200614, 32123317, 21895641, 12938084)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586564	SCV000695612	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2017-08-25	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.7916A>G (p.Tyr2639Cys) variant involves the alteration of a conserved amino acid residue located in the EGF-like calcium-binding domain (IPR001881) (InterPro). Cysteine residues are critical in stabilization of EGF-like domains in fibrillin, thus introducing a new cysteine residue is predicted to disturb disulphide bonding and affect protein stability (Aalberts 2010). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however these have not been investigated by functional studies. This variant has been reported in multiple patients affected by the Marfan syndrome spectrum, with a strong family history of which many fulfilled the Ghent diagnostic criteria (Aalberts 2010, Poninska 2016). This variant is absent in 121400 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV000770653	SCV000738915	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2017-07-25	criteria provided, single submitter	clinical testing	The p.Y2639C pathogenic mutation (also known as c.7916A>G), located in coding exon 63 of the FBN1 gene, results from an A to G substitution at nucleotide position 7916. The tyrosine at codon 2639 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in a cbEGF-like 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 alteration has been reported in several individuals with a clinical diagnosis of Marfan syndrome (MFS) as well as in a number of MFS cohorts (Mátyás G et al. Hum. Mutat. 2002;19:443-56; Voermans Nc et al. Clin. Genet. 2009;76:25-37; Aalberts JJ et al. Neth Heart J. 2010;18:85-9; Robinson DO et al. Clin. Genet. 2012;82:223-31; Attanasio M et al. Eur J Med Genet. 2013;56:356-60). In addition, this alteration segregated with disease in a large, 4-generation Dutch pedigree and in a small Polish family (Aalberts JJ et al. Neth Heart J. 2010;18:85-9; Poninska JK et al. J Transl Med. 2016;14:115). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770653	SCV000902111	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-11-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000181620	SCV002017728	likely pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000663995	SCV002025467	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS5, PP4
Mayo Clinic Laboratories, Mayo Clinic	RCV000181620	SCV002103255	pathogenic	not provided	2021-09-23	criteria provided, single submitter	clinical testing	PP1_strong, PP2, PP3, PM1, PM2, PS4_moderate
Invitae	RCV002515309	SCV003442912	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-10	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. ClinVar contains an entry for this variant (Variation ID: 200123). This missense change has been observed in individuals with Marfan syndrome or thoracic aortic aneurysm and dissection (PMID: 20200614, 27146836). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2639 of the FBN1 protein (p.Tyr2639Cys).
Center for Medical Genetics Ghent, University of Ghent	RCV000663995	SCV000787379	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing