ClinVar Genomic variation as it relates to human health

Variant summary: FGB c.498_512del15 (p.Asn167_Glu171del), also referred to as fibrinogen Epsom, results in an in-frame deletion that is predicted to remove five amino acids from the fibrinogen, alpha/beta/gamma chain, coiled coil domain (IPR012290) of the encoded protein. The variant was absent in 249990 control chromosomes (gnomAD). c.498_512del15 has been reported in the literature in the heterozygous state in individuals affected with Congenital Hypodysfibrinogenemia who exhibited below normal functional fibrinogen levels and prolonged thrombin clotting times (Brennan_2009, Shen_2011). The variant segregated with this phenotype in three affected individuals in a single family who were predominately asymptommatic, but the affected mother of the proband had a considerable history of pregnancy-associated bleeding and miscarriage in the first trimester (Brennan_2009). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19229055, 21959590). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The FGB c.498_512del15 variant is predicted to result in an in-frame deletion (p.Asn167_Glu171del). This variant has been reported in the heterozygous state in individuals who presented with pregnancy-associated bleeding or provoked deep venous thrombosis (Brennan et al. 2009. PubMed ID: 19229055; Shen et al. 2011. PubMed ID: 21959590, referred to as fibrinogen Epsom). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.