ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7540G>A (p.Gly2514Arg) (rs363811)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000245416 SCV000319359 uncertain significance Cardiovascular phenotype 2015-09-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Blueprint Genetics RCV000208039 SCV000263911 likely pathogenic Marfan syndrome 2015-09-15 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000208039 SCV000787339 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000766960 SCV000513006 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing The G2514R variant of uncertain significance in the FBN1 gene has been reported previously in association with Marfan syndrome and sporadic TAAD, however detailed clinical and family segregation information were not provided (Ng et al., 2002; Pilop et al., 2009; Guo et al., 2015). This 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 G2514R 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, although the G2514R variant occurs within one of the calcium-binding EGF-like domains, this variant does not affect a Cysteine residue. Cysteine substitutions in these domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003).
Invitae RCV000470522 SCV000544943 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2016-10-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2514 of the FBN1 protein (p.Gly2514Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in the ExAC population database (rs363811, ExAC no frequency), but is present in some individuals in the HapMap project. This variant has been reported in two individuals affected with Marfan syndrome (PMID: 11875032, 19720936) and in one individual with sporadic thoracic aortic aneurysms and dissections (PMID: 26272055). ClinVar contains an entry for this variant (Variation ID: 178034). 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 C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function and splicing. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154717 SCV000204397 uncertain significance not specified 2013-08-22 criteria provided, single submitter clinical testing The Gly2514Arg variant in FBN1 has been reported in two individuals with Marfan syndrome (Ng 2002, Kumar 2009, Pilop 2009). In addition, this variant has been i dentified in 0.6% (3/336) of Asian chromosomes, 0.6% (1/180) of Luhya Kenyan chr omosomes, 2% (2/98) of Mexican chromosomes, and 0.6% (1/176) of Tuscan chromosom es by the HapMap Project (dbSNP rs363811). Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly2514Arg variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. Furthermore, this variant has segre gated between a mother and daughter with clinical features of Marfan syndrome (L MM unpublished data), suggesting a pathogenic role. In summary, due to the confl icting information available, additional studies are needed to fully assess the clinical significance of the Gly2514Arg variant.

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