ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.718C>T (p.Arg240Cys) (rs137854480)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000017925 SCV000052427 pathogenic Ectopia lentis, isolated, autosomal dominant 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000017924 SCV000058916 pathogenic Marfan syndrome 2008-06-30 criteria provided, single submitter clinical testing
GeneDx RCV000181681 SCV000233984 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing The R240C pathogenic variant in the FBN1 gene has been reported in individuals with a diagnosis of Marfan syndrome (Loeys et al. 2001; Stheneur et al 2009) and in individuals with isolated ectopia lentis (Comeglio et al., 2002; Korkko et al., 2002; Biggin et al., 2004; Vanita et al., 2007; Aragon-Martin et al., 2010). In addition, R240C segregated with disease in several families with familial ectopia lentis (Korkko et al., 2002; Vanita et al., 2007). The R240C variant results in 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. The R240C variant introduces a cysteine residue within the TGF-binding protein domain 1 of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Studies have shown that missense variants in the FBN1 gene that substitute or produce cysteine are associated with a higher risk for ectopia lentis than other missense variants (Faivre et al., 2007; Jin et al 2007). Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, the R240C variant is not observed in large population cohorts (Lek et al., 2016).In summary, R240C in the FBN1 gene is interpreted as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000515367 SCV000611194 pathogenic Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2017-05-18 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000017924 SCV000678236 pathogenic Marfan syndrome 2017-08-01 criteria provided, single submitter clinical testing FBN1:NM_000138.4:exon7 p.Arg240Cys (c.718C>T): This variant has been reported in >5 individuals with Marfan syndrome, features of Marfan syndrome or isolated ectopia lentis (Loeys 2001 PMID11700157, Comeglio 2002 PMID 12446365, Korkko 2002 PMID11826022, Ades 2004 15054843, Vanita 2007 18079676, Stheneur 2009 PMID 19293843). This variant segregated with isolated ectopia lentis in >10 family members from 2 different families (Ades 2004 PMID 15054843, Vanita 2007 PMID 18079676). This variant is absent from large population studies and has been reported by multiple laboratories as pathogenic in ClinVar (Variant ID:16461). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant is predicted to affect a cysteine residue. Cysteine in the FBN1 gene is reported to have important functional relevance; variants that involve a cysteine residue are reported to be particularly significant (Dietz, PMID: 20301510). In summary, this variant is classified as pathogenic based on presence of affected individuals, segregation data, absence from controls, and predicted variant impact to the protein.
Invitae RCV000631968 SCV000753071 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 240 of the FBN1 protein (p.Arg240Cys). 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 (ExAC no frequency). This variant has been reported to segregate with ectopia lentis in two families and has been reported in individuals affected with this conditon (PMID: 15054843, 18079676, 20564469, 11826022, 17657824) and with classical Marfan syndrome (PMID: 11700157, 19293843). ClinVar contains an entry for this variant (Variation ID: 16461). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics,University Medical Center Hamburg-Eppendorf RCV000017924 SCV000897654 likely pathogenic Marfan syndrome 2018-11-20 criteria provided, single submitter clinical testing
OMIM RCV000017924 SCV000038203 pathogenic Marfan syndrome 2010-03-17 no assertion criteria provided literature only
OMIM RCV000017925 SCV000056640 pathogenic Ectopia lentis, isolated, autosomal dominant 2010-03-17 no assertion criteria provided literature only
Center for Medical Genetics Ghent,University of Ghent RCV000017924 SCV000787308 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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