ClinVar Genomic variation as it relates to human health

Fibrinogen Metz has also been called fibrinogen Bergamo-1, Hershey-2, Hershey-3, Homburg-2, Homburg-3, Kawaguchi-1, Ledyard, Leogan, New Albany, Osaka-1, Schwarzach-1, Stony Brook-1, Torino-1, Zurich-1, and Milano XII digenic. Fibrinogen Metz is an arg16-to-cys (R16C) substitution in the fibrinogen alpha chain (Henschen et al., 1981). See also Southan et al. (1982), Henschen et al. (1983), Reber et al. (1985), Miyashita et al. (1985), and Miyata et al. (1987). Galanakis et al. (1989) stated that 52 dysfibrinogens had been structurally characterized and that most were single amino acid substitutions with a high frequency of substitutions at arg positions A-alpha-16, A-alpha-19, B-beta-14, and gamma-275. Galanakis et al. (1989) described an R16C substitution in fibrinogen Stony Brook and described the functional characteristics of the variant. According to Galanakis (1993), this mutation has been identified in 15 unrelated families. In 2 of these, an arg16-to-his (R16H; 134820.0004) mutation was detected by both DNA and protein sequencing. Lee et al. (1991) found the R16C variant, which they called fibrinogen Ledyard, in a 10-year-old boy with a history of mild bleeding whose father had the same defect and a history of bleeding after surgery. Both patients were heterozygous. Bolliger-Stucki et al. (2001) described an anomalous fibrinogen called Milano XII in an asymptomatic Italian woman, and demonstrated that its basis was double heterozygosity for the R16C mutation in exon 2 of the FGA gene, and a G165R mutation in the FGG gene (134850.0018). The woman's condition was discovered when routine coagulation test results showed a prolonged thrombin time. Fibrinogen levels in functional assays were considerably lower than levels in immunologic assays. Bolliger-Stucki et al. (2001) concluded that the FGA mutation was mainly responsible for the coagulation abnormalities, whereas the change in the FGG gene was responsible for a conformational change in the D3 fragment. The R16C mutation of the FGA gene is a common cause of dysfibrinogenemia (616004) and is associated with both bleeding and thrombosis. Flood et al. (2006) proposed to understand the mechanism of the thrombotic phenotype. They studied a young patient with dysfibrinogenemia (fibrinogen Hershey III) who was found to be heterozygous for the R16C mutation. Functional assays were performed on purified fibrinogen to characterize clot formation and lysis with plasmin and trypsin. Consistent with previous results, clot formation was diminished, but unexpectedly, fibrinolysis was also delayed. When clot lysis was assayed with trypsin substituted for plasminogen, a significant delay was also observed, indicating that defective binding to plasminogen could not explain the fibrinolytic resistance. The results suggested that the defective fibrinolysis is due to increased proteolytic resistance, most likely reflecting changes in clot structure. Flood et al. (2006) stated that the R16C mutation is the most common fibrinogen mutation in humans. Although about 30% of the reported cases of the R16C mutation in humans are associated with hemorrhage, some 15% of reported cases are associated with thrombosis (Hanss and Biot, 2001). (less)