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In a three-generation family presenting with recurrent arterial and venous thrombosis, a heterozygous FGA missense variant c.259A>C (p.Lys87Gln) was identified by whole exome sequencing and confirmed by Sanger analysis in all three affected siblings, with absence of other known thrombophilia markers (PMID:30881084). The variant is exceedingly rare (ExAC = 0.000008) and predicted to be damaging by six of seven in silico algorithms; structural modeling of the fibrinogen alpha chain suggests perturbation of polymerization interfaces.
The pedigree is consistent with autosomal dominant inheritance with full penetrance among carriers. Segregation analysis showed co-segregation in two additional affected relatives beyond the proband, supporting a causal role. No independent cohorts or functional coagulation assays have yet been reported. Computational and modeling data provide supporting functional evidence but additional biochemical or animal model studies are needed to confirm pathogenic mechanism.
Key Take-Home: The FGA c.259A>C (p.Lys87Gln) variant co-segregates with familial thrombophilia and represents a candidate AD risk allele that may inform genetic testing in unexplained thrombotic pedigrees.
Gene–Disease AssociationLimitedSingle pedigree with three affected carriers co-segregation in one family Genetic EvidenceLimitedOne family with 3 probands and segregation in two additional relatives Functional EvidenceSupportingIn silico predictions and structural modeling concordant with deleterious effect |