ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.364C>T (p.Arg122Cys) (rs137854467)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620673 SCV000738914 pathogenic Cardiovascular phenotype 2017-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Blueprint Genetics RCV000181647 SCV000927817 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000029732 SCV000786986 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626614 SCV000747315 pathogenic High palate; Arachnodactyly; Lens subluxation; Aortic dissection 2017-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000181647 SCV000233950 pathogenic not provided 2018-08-30 criteria provided, single submitter clinical testing The R122C pathogenic variant in the FBN1 gene has been reported in multiple individuals with Marfan syndrome or ectopia lentis (Stahl-Hallengren et al., 1994; Black et al., 1998; Loeys et al., 2001; Comeglio et al., 2002; Jin et al., 2007; Jin et al., 2008; Hung et al., 2009; Zadeh et al., 2011; Wang et al., 2013; Li et al., 2014; Castro et al., 2017). This variant has segregated with FBN1-related phenotypes in several families (Stahl-Hallengren et al., 1994; Black et al., 1998). Additionally, the R122C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The R122C 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 and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, the R122C variant introduces a cysteine residue within an EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein.
Integrated Genetics/Laboratory Corporation of America RCV000029732 SCV000052385 pathogenic Marfan syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000029732 SCV000544955 pathogenic Marfan syndrome 2016-08-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 122 of the FBN1 protein (p.Arg122Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs137854467, ExAC no frequency). This variant has been reported in the literature to segregate with disease in two families (PMID: 8040326, 9452085), as well as in multiple unrelated individuals affected with ectopia lentis and/or Marfan syndrome (PMID: 17679947, 12446365, 25053872, 21932315, 22772377, 21895641, 11700157). ClinVar contains an entry for this variant (Variation ID: 16440). 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"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017902 SCV000038181 pathogenic Marfan syndrome, atypical 1994-08-01 no assertion criteria provided literature only

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