ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4214T>G (p.Leu1405Arg) (rs767606368)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757265 SCV000885420 likely benign not provided 2017-06-27 criteria provided, single submitter clinical testing The FBN1 c.4214T>G, p.Leu1405Arg variant was previously detected in a healthy adult tested at ARUP. It has been reported three times in the medical literature: in association with a connective tissue disorder with vascular involvement (Rybczynski et al., 2008), in association with adolescent idiopathic scoliosis (Buchan et al., 2014), and as a de novo variant in a patient with spontaneous coronary artery dissection (von Hundelshausen et al., 2015). However, this variant is found in the genome Aggregation Database with a general population frequency of 0.01% (30 out of 277,184 chromosomes), while ClinVar lists it as a variant of uncertain significance (ClinVar ID 200041). The majority of pathogenic missense mutations associated with Marfan syndrome involve alterations to conserved residues in critical EFG-like domains, and although this variant is located in one of these domains, it is not within the EGF consensus sequence defined in the Ghent criteria (Loeys 2010). Computational algorithms make conflicting predictions as to its effect on protein structure and function (SIFT: tolerated, Poly-Phen 2: benign, Mutation Taster: disease causing). Based on all available evidence, the c.4214T>G variant is likely to be benign.
Center for Medical Genetics Ghent,University of Ghent RCV000663701 SCV000787034 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000505775 SCV000233816 uncertain significance not specified 2016-12-02 criteria provided, single submitter clinical testing The L1405R variant in the FBN1 gene has been reported in one patient with a connective tissue disease with vascular involvement and in one individual with adolescent idiopathic scoliosis who did not meet criteria for Marfan syndrome (Rybczynski et al., 2008; Buchan et al., 2014). In addition, the L1405R variant has been reported as a de novo variant in a 46 year old male with spontaneous coronary artery dissection (von Hundelshausen et al., 2015). The L1405R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L1405R 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. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, although the L1405R variant is located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a Cysteine residue within this domain. 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). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000505775 SCV000919336 uncertain significance not specified 2018-08-21 criteria provided, single submitter clinical testing Variant summary: FBN1 c.4214T>G (p.Leu1405Arg) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 0.00011 in 277184 control chromosomes (gnomAD). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.4214T>G, has been reported in the literature in individuals affected with Aortopathy (Rybczynski_2008). In particular, Von Hundelshausen_2015 reports the variant to be a de novo occurrence in a SCAD patient and authors suggest the variant could have reduced penetrance. These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. In addition, literature, Haller_2015, reports the variant to occur in a patient diagnosed with adolescent idiopathic scoliosis and was present in her brother who had pectus excavatum and mild scolosis, while the mother who was unaffected also carried the variant of interest; none of the family members presented with a cardiac phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as "VUS - possibly benign."
Invitae RCV000471621 SCV000544946 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-05-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 1405 of the FBN1 protein (p.Leu1405Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs767606368, ExAC 0.01%). This variant has been reported in an individual affected with a FBN1-related connective tissue disease (PMID: 19012347) and in an individual with adolescent scoliosis (PMID: 26333736). In addition, this variant has been shown to arise de novo in an individual affected with a spontaneous coronary artery dissection without other FBN1-related symptoms (PMID: 25519456). The article notes that this variant was also observed in several in-house exomes, including in children without known vascular manifestations, though the clinical significance of this is uncertain. This variant has been reported in individuals in the Universal Mutation Database (PMID: 12938084) and has an entry in ClinVar (Variant ID: 200041). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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