ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1027G>A (p.Gly343Arg) (rs146726731)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000181421 SCV000603613 uncertain significance not specified 2016-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617536 SCV000738749 uncertain significance Cardiovascular phenotype 2016-12-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148500 SCV000190209 uncertain significance Marfan syndrome 2014-06-01 no assertion criteria provided research
Center for Human Genetics, Inc RCV000659507 SCV000781327 uncertain significance Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000393542 SCV000904495 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-10-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the TGFbeta-like motif 2 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a few individuals suspected of having Marfan syndrome (PMID: 17253931, 17663468, 24311428). This variant has also been identified in 51/277040 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
GeneDx RCV000588674 SCV000233723 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing The G343R variant of uncertain significance in the FBN1 gene has been reported previously in a cohort of patients with suspected Marfan syndrome (Tjeldhorn et al., 2006). This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The G343R 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. Additionally, this substitution occurs at a position that is conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with FBN1-related. Moreover, the G343R variant does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1/FBN2 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent themajority of pathogenic missense changes associated with FBN1-related disorders (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.
Illumina Clinical Services Laboratory,Illumina RCV000393539 SCV000392626 likely benign Stiff skin syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000284823 SCV000392627 likely benign Acromicric dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000148500 SCV000392628 likely benign Marfan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000393542 SCV000392629 likely benign Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000307377 SCV000392630 likely benign Geleophysic dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000364336 SCV000392631 likely benign Weill-Marchesani syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000404755 SCV000392632 likely benign MASS syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000315057 SCV000392633 likely benign Ectopia lentis 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588674 SCV000695447 likely benign not provided 2017-08-22 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.1027G>A (p.Gly343Arg) variant involves the alteration of a conserved nucleotide, resulting in a missense change in a TB domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in ExAC and control cohorts from the literature at a frequency of 0.0001565 (19/121412 control chromosomes), which is slightly above (~1.5 times) the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this variant may be a benign polymorphism. While several studies identified the variant in patients without strong evidence for causality, one family study found the variant co-occurring with a reportedly pathogenic COL3A1 variant (p.G324S), and another affected family member did not carry the variant of interest (Grond-Ginsbach_2017), further supporting a benign impact for the variant. Multiple clinical diagnostic laboratories/reputable databases classified this variant with conflicting interpretations, including uncertain significance and likely benign. Taken together, this variant is classified as likely benign.
Invitae RCV000463596 SCV000544839 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-09-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 343 of the FBN1 protein (p.Gly343Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs146726731, ExAC 0.04%). This variant has been reported in the literature in individuals suspected of being affected with Marfan syndrome (PMID: 17253931, 24311428, 17663468). ClinVar contains an entry for this variant (Variation ID: 161244). 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: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.