ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1948C>T (p.Arg650Cys) (rs193922185)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507859 SCV000603634 pathogenic not specified 2016-09-19 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000029702 SCV000786812 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763357 SCV000894047 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 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000493360 SCV000582280 pathogenic not provided 2018-03-20 criteria provided, single submitter clinical testing The R650C variant in the FBN1 gene has been reported in one individual with bilateral ectopia lentis, absent uvula, and aortic root measurements in the upper limits of normal (Zadeh et al., 2011). This variant has also been reported in a 6-year-old male with isolated ectopia lentis and, although this variant was inherited from his unaffected mother, ectopia lentis is present in seven additional maternal relatives (Zhang et al., 2015). Additionally, the R650C variant has been reported in 31 individuals from nine unrelated families, and while individuals who harbor this variant primarily have ectopia lentis they also have an increased risk for aortic dilation (Vatti et al., 2017). Furthermore, the R650C variant is not observed in large population cohorts (Lek et al., 2016). The R650C 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. In addition, the R650C variant introduces a new cysteine (C) residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003). Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Integrated Genetics/Laboratory Corporation of America RCV000029702 SCV000052355 likely pathogenic Marfan syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV000631908 SCV000753011 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-07-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 650 of the FBN1 protein (p.Arg650Cys). 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 in several individuals affected with ectopia lentis (PMID: 21932315, 25900864). ClinVar contains an entry for this variant (Variation ID: 36042). 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 individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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