ClinVar

Description

The F7 c.1091G>A variant is predicted to result in the amino acid substitution p.Arg364Gln. This variant is also described using legacy nomenclature as p.Arg304Gln, has been reported to be causative for autosomal recessive factor VII deficiency in several patients with varying clinical phenotypes ranging from asymptomatic to mild bleeding or severe bleeding after trauma (Girolami et al. 2011. PubMed ID: 21902896; Kirkel et al. 2010. PubMed ID: 20040857; O’Brien et al. 1991. PubMed ID: 2070047). Most patients with the p.Arg364Gln variant showed prolonged prothrombin times (PT); however, PT results using F7 protein with this variant are variable – ranging from severely reduced to normal – depending upon the source of substrate used for the biochemical test (O’Brien et al. 1991. PubMed ID: 2070047; Cristiani et al. 2013. PubMed ID: 24711753). The p.Arg364Gln substitution does not appear to alter F7 protein levels, rather, it appears to alter substrate binding (see for example O’Brien et al. 1991. PubMed ID: 2070047; Cristiani et al. 2013. PubMed ID: 24711753). Other substitutions of amino acid p.Arg364 have been reported in patients with Factor VII deficiency (e.g. p.Arg364Trp, Matsushita et al. 1994. PubMed ID: 8125953, Cristiani et al. 2013. PubMed ID: 24711753) suggesting that amino acid residue p.Arg364 is important for proper F7 protein function. Given all the evidence, we interpret c.1091G>A (p.Arg364Gln) as pathogenic.