ClinVar

Description

Variant summary: FBN1 c.1879C>T (p.Arg627Cys) results in a non-conservative amino acid change located in the cb EGF-like #06 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Missense affecting/creating cysteine residues and affecting the conserved residues of the EGF-consensus sequence are among the criteria considered as causal in making a diagnosis of Marfan syndrome The variant was absent in 251538 control chromosomes. c.1879C>T has been widely reported in the literature in multiple individuals affected with features of Marfan Syndrome and has subsequently been cited by others (example, Hayward_1994, Hayward_1997, Rommel_2005, Miyazawa_2007, Waldmuller_2007, Jin_2007, Halliday_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in enhanced proteolytic susceptibility to a variety of proteases (example, Vollbrandt_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.