Submissions for variant NM_000138.5(FBN1):c.59A>G (p.Tyr20Cys)

gnomAD frequency: 0.00016  dbSNP: rs201309310

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000148501	SCV003762191	uncertain significance	Marfan syndrome	2022-12-01	reviewed by expert panel	curation	The NM_000138 c.59A>G, is a missense variant in FBN1 predicted to cause a substitution of a Tyrosine by a Cysteine at amino acid 20 (p.Tyr20Cys). This variant was found in a proband with aortic root dilatation and a systemic score of 7 or above which is a highly specific phenotype for Marfan syndrome, however, a pathogenic splice variant in FBN1 was also identified in cis in this individual (BP2). The variant segregates with the disease in 4 affected family members, who also carry the pathogenic splice variant in FBN1. The variant in FBN1 has been reported 12 times in ClinVar: 3 times as likely benign, 8 times as uncertain significance and once as likely pathogenic (Variation ID: 161245). This variant has been identified in 37 individuals of European non-Finnish origin (MAF: 0.029%) (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments, PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2
Eurofins Ntd Llc (ga)	RCV000587403	SCV000227023	uncertain significance	not provided	2015-01-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000587403	SCV000233704	uncertain significance	not provided	2022-02-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; 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: 25812041, 25637381, 26017485, 16222657, 24941995, 29543232, 12938084)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000181402	SCV000539151	uncertain significance	not specified	2016-03-31	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple papers report as VUS; ExAC: 16/66648 Europeans; ClinVar: 1 LB, 2 VUS
Invitae	RCV000545272	SCV000627947	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587403	SCV000695575	likely benign	not provided	2017-07-20	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.59A>G (p.Tyr20Cys) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 41/277062 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003 (38/126638). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in multiple affected individuals without strong evidence for causality. Although, one paper, Yang_2014 indicates the variant does segregate with disease in the family, however, clinical information is not provided for additional family members. In addition, multiple clinical diagnostic laboratories/reputable databases and publications classified this variant with conflicting classifications "uncertain significance" or "likely benign." Taken together, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000587403	SCV001149473	uncertain significance	not provided	2016-05-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000604732	SCV001349837	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-01-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000604732	SCV002042005	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000604732	SCV002657151	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-01-07	criteria provided, single submitter	clinical testing	The p.Y20C variant (also known as c.59A>G), located in coding exon 1 of the FBN1 gene, results from an A to G substitution at nucleotide position 59. The tyrosine at codon 20 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the signal peptide domain. This alteration has been reported in an individual with skeletal involvement and pneumothorax as well as individuals with abdominal and thoracic aortic aneurysms (Arbustini E et al. Hum Mutat, 2005 Nov;26:494; van de Luijtgaarden KM et al. Hum Genet, 2015 Aug;134:881-93; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). 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 amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CSER _CC_NCGL, University of Washington	RCV000148501	SCV000190210	uncertain significance	Marfan syndrome	2014-06-01	no assertion criteria provided	research
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000604732	SCV000731233	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587403	SCV001740151	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587403	SCV001964116	uncertain significance	not provided		no assertion criteria provided	clinical testing