Submissions for variant NM_000138.5(FBN1):c.3302A>G (p.Tyr1101Cys)

dbSNP: rs1555398625

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770677	SCV000902139	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-10-30	criteria provided, single submitter	clinical testing
Invitae	RCV000808781	SCV000948901	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-02-23	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 1101 of the FBN1 protein (p.Tyr1101Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 11700157, 12402346, 16222657, 16596670, 19863550, 28941062). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 549154). 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. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000663628	SCV001428526	pathogenic	Marfan syndrome	2018-08-06	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000663628	SCV002025572	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS5, PP4
Ambry Genetics	RCV000770677	SCV002607082	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-06-18	criteria provided, single submitter	clinical testing	The p.Y1101C pathogenic mutation (also known as c.3302A>G), located in coding exon 26 of the FBN1 gene, results from an A to G substitution at nucleotide position 3302. The tyrosine at codon 1101 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #12 domain. This alteration has been reported in subjects with Marfan syndrome and has been reported as de novo in several cases (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Rommel K et al. Hum. Mutat., 2002 Nov;20:406-7; Biggin A et al. Hum. Mutat., 2004 Jan;23:99; Arbustini E et al. Hum. Mutat., 2005 Nov;26:494; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8; Yoo EH et al. Clin. Genet., 2010 Feb;77:177-82). 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 was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV003329321	SCV004036295	likely pathogenic	not provided	2023-03-22	criteria provided, single submitter	clinical testing	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 (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12938084, 35058154, 11700157, 31730815)
Center for Medical Genetics Ghent, University of Ghent	RCV000663628	SCV000786950	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing