ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.59A>G (p.Tyr20Cys) (rs201309310)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587403 SCV000227023 uncertain significance not provided 2015-01-09 criteria provided, single submitter clinical testing
GeneDx RCV000587403 SCV000233704 uncertain significance not provided 2017-02-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN1 gene. The Y20C variant has been reported in one patient who had features suggestive of Marfan syndrome and in one patient with sporadic abdominal aortic aneurysm (Arbustini et al., 2005; van de Luijtgaarden et al., 2015); however, segregation information and functional studies were not included. Furthermore, this substitution occurs at a position that is only conserved in mammals and where cysteine as the wild type in at least one mammalian species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, the Y20C variant 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 Marfan syndrome (Collod-Beroud et al., 2003). Nevertheless, the Y20C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.
Laboratory for Molecular Medicine,Partners HealthCare 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 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-05-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 20 of the FBN1 protein (p.Tyr20Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs201309310, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual with skeletal abnormalities and pneumothorax and an individual affected with abdominal aortic aneurysm (PMID: 16222657, 26017485). ClinVar contains an entry for this variant (Variation ID: 161245). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America 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.
CSER_CC_NCGL; University of Washington Medical Center 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 Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research

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