ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1879C>T (p.Arg627Cys) (rs727503057)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767974 SCV000898701 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 2018-10-19 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon 15 p.Arg627Cys (c.1879C>T): This variant has been reported in the literature in at least 10 individuals with a diagnosis, clinical suspicion or primary feature of Marfan syndrome, one of whom was reported as a de novo (Hayward 1994 PMID:8004112, Halliday 2002 PMID:12161601, Rommel 2005 PMID:16220557, Jin 2007 PMID:17679947, Miyazawa 2007 PMID:17503327, Waldmuller 2007 PMID:17418587, Stheneur 2009 PMID:19293843, Attanasio 2013 PMID:23684891, Campens 2015 PMID:25644172). This variant segregated with disease in at least 6 affected family members (Rommel 2005 PMID:16220557, Miyazawa 2007 PMID:17503327). This variant is not present in large control databases but is present in Clinvar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:163480). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies also support that this variant will impact the protein (Vollbrandt 2004 PMID:15161917, Kirschner 2011 PMID:21784848). 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 the data above (multiple probands, segregation studies, presence of a de novo, absence from controls and impact to protein).
Center for Medical Genetics Ghent,University of Ghent RCV000150704 SCV000786808 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Invitae RCV000524497 SCV000544843 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 627 of the FBN1 protein (p.Arg627Cys). 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 (rs727503057, ExAC no frequency). This variant has been reported in several individuals diagnosed with Marfan syndrome (PMID: 8004112, 16220557, 23684891), as well as isolated ectopia lentis (PMID: 12161601) and suspicion of Marfan syndrome (PMID: 17418587, 17679947, 25644172). ClinVar contains an entry for this variant (Variation ID: 163480). Experimental studies have shown that this missense change leads to increased susceptibility to proteolytic degradation (PMID: 15161917, 21784848). This variant generates a cysteine residue in an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 4750422, 16677079). Cysteine creating variants in these domains have been shown to affect protein stability and are overrepresented among patients with Marfan syndrome (PMID: 15161917, 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150704 SCV000198104 pathogenic Marfan syndrome 2014-10-30 criteria provided, single submitter clinical testing The p.Arg627Cys variant in FBN1 has been reported in 1 individual with Ectopia L entis (Jin 2007) and 9 individuals with Marfan syndrome, including 1 individual in whom the variant occurred de novo. The variant segregated with Marfan syndrom e in 9 affected relatives from 4 families (Hayward 1994, Halliday 2002, Rommel 2 005, Waldmuller 2007, Miyazawa 2007, Stheneur 2009, Attanasio 2013). In one of t hese families, this variant was also observed in 3 asymptomatic individuals; how ever, they were not clinically evaluated for the study (Miyazawa 2007). The vari ant was absent from large population studies. In vitro functional studies provid e some evidence that this variant may impact protein function (Kirschner 2011). However, these types of assays may not accurately represent biological function. In summary, the p.Arg627Cys variant meets our criteria to be classified as path ogenic for Marfan syndrome in an autosomal dominant manner (http://www.partners. org/personalizedmedicine/LMM) based upon segregation studies, absence from contr ols, and functional evidence.
Petrovsky Russian Research Center of Surgery, The Federal Agency for Scientific Organizations RCV000150704 SCV000986692 pathogenic Marfan syndrome 2019-08-19 criteria provided, single submitter curation The p.Arg627Cys is a well known missense variant reported in various individuals (PMID: 8004112, 16220557, 23684891, 12161601, 17418587, 17679947, 25644172, 20591885; DOI: 10.3760/cma.j.issn.1003-9406.2019.06.008), with a frequency of A=0.00001 (1/125568, TOPMED)(ExAC no frequency). This variant has been reported several times in ClinVar (Variation ID: 163480) with a well-established Pathogenic classification. The p.Arg627Cys substitution occurs in the cbEGF-like domain. In FBN1 gene missense affecting/creating cysteine residues is one of the criteria for pathogenic mutations (PMID: 20591885).

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