ClinVar Miner

Submissions for variant NM_000131.4(F7):c.1091G>A (p.Arg364Gln) (rs121964926)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000479479 SCV000857897 other not provided 2017-10-30 criteria provided, single submitter clinical testing
GeneDx RCV000479479 SCV000568816 pathogenic not provided 2017-03-16 criteria provided, single submitter clinical testing The R364Q variant in the F7 gene has been reported previously in multiple individuals, sometimes using alternate nomenclature of R304Q, and referred to as F7-Padua (Stenson et al., 2014; Rabelo et al., 2015). In a review of 27 individuals homozygous for the R364Q variant, 16 were asymptomatic, 1 was asymptomatic except for severe bleeding after a Cesarean-section, 9 showed a mild bleeding tendency, and 1 had no clinical info provided (Girolami et al., 2011). Although most individuals with FVII deficiency due to R364Q exhibit prolonged prothrombin times (PT) and F7 activity below 10% using rabbit brain thromboplastin, most exhibit normal PT and F7 activity using ox brain thromboplastin, and intermediate values with human brain thromboplastin (Kirkel et al., 2010). However, purified FVII protein from one individual homozygous for R364Q exhibited no detectable FVII clotting activity (O'Brien et al., 1991). Although not present in the homozygous state in any control individuals, the R364Q variant is observed in 41/9,952 alleles (0.41%) from individuals of African descent in the ExAC dataset (Lek et al., 2016). The R364Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this substitution occurs at a position that is conserved across species. Missense variants in the same (R364W) and nearby (N361I, P363T, P363H, and M366V) residues have been reported in the Human Gene Mutation Database in association with factor VII deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R364Q as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000779130 SCV000915625 pathogenic Factor VII deficiency 2018-10-23 criteria provided, single submitter clinical testing The F7 c.1091G>A (p.Arg364Gln) missense variant, also commonly referred to in the literature as p.Arg304Gln or the "Pauda" variant, has been reported in at least eight studies in which it is identified in at least 70 individuals, including 11 clinically symptomatic homozygotes and two clinically symptomatic compound heterozygotes (Ding et al. 2003; Marty et al. 2008; Girolami et al. 2011; Rabelo et al. 2015). The p.Arg364Gln variant has also been reported in at least 19 clinically asymptomatic homozygotes with lower factor VII activity than wildtype (O'Brien et al. 1991; Girolami et al. 2011; Rabelo et al. 2015). The variant is present at a frequency of 0.00908 in the African population of the 1000 Genomes Project. This allele frequency is high but may be consistent with disease prevalence and the fact that many individuals with factor VII deficiency are clinically asymptomatic. Girolami et al. (2011) found the mean levels of activated FVII in six homozygotes to be significantly lower than the activated FVII levels in 21 normal controls. Further, the variant was associated with reduced factor VII activity when assayed with rabbit brain thromboplastin, however, the activity levels varied between the use of human placenta, recombinant human or ox-brain thromboplastin (O'Brien et al. 1991; Kirkel et al. 2010; Girolami et al. 2011; Girolami et al. 2011; Rabelo et al. 2015). Based on the collective evidence, the p.Arg364Gln variant is classified as a pathogenic risk factor for factor VII deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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