ClinVar Miner

Submissions for variant NM_000131.4(F7):c.1061C>T (p.Ala354Val) (rs36209567)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000012857 SCV000915624 pathogenic Factor VII deficiency 2018-08-15 criteria provided, single submitter clinical testing The F7 c.1061C>T (p.Ala354Val) missense variant, previously known as p.Ala294Val, has been reported in more than seven studies in which it is found in a total of more than 97 alleles in individuals with factor VII deficiency, including 10 homozygotes and four compound heterozygotes (Bernardi et al. 1994; Wulff et al. 2000; Fromovich-Amit et al. 2004; Mariani et al. 2005; Marty et al. 2008; Branchini et al. 2012; Pavlova et al. 2015). Of note, this variant is also described in cis with a second variant, c.11128delC, in an additional 111 alleles in affected individuals, including 26 individuals homozygous for both variants. The p.Ala354Val variant was absent from 20 controls, but is reported at a frequency of 0.00128 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional analysis of FVII activity in the plasma of a homozygous individual carrying this variant and the second variant, c.11128delC, showed drastically reduced activity. In vivo studies of the p.Ala354Val variant identified decreased activation of FX by variant FVII protein; however, functional studies showed discordant results when evaluating alterations in the variant protein's interaction with activators and cofactors (Toso et al. 2002; Fromovich-Amit et al. 2004; Branchini et al. 2012). Based on the evidence, the p.Ala354Val variant is classified as pathogenic for factor VII deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000012857 SCV000899413 pathogenic Factor VII deficiency 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851974 SCV000899414 likely pathogenic Abnormal bleeding 2019-02-01 criteria provided, single submitter research
OMIM RCV000012857 SCV000033098 pathogenic Factor VII deficiency 2000-01-01 no assertion criteria provided literature only

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