ClinVar Miner

Submissions for variant NM_000128.3(F11):c.1199C>T (p.Pro400Leu) (rs533335580)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000428449 SCV000521313 likely pathogenic not provided 2016-12-23 criteria provided, single submitter clinical testing The P400L variant in the F11 gene has been reported previously, using alternate nomenclature P382L, in association with factor XI deficiency, in affected individuals who were compound heterozygous for the P400L variant and another variant (Quélin et al., 2005; Mitchell et al., 2006). The P400L variant has also been reported in an individual with mild factor XI deficiency who was heterozygous for the P400L variant with no second variant identified (Castaman et al., 2014). The P400L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P400L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby residues (R396C, W399L, P400T, W401R, V403M, T404N) have been reported in the Human Gene Mutation Database in association with factor XI deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. In addition, the P400L variant belongs to the SP domain, within the loop to beta-B, where other variants associated with factor XI deficiency have been reported (Saunders et al., 2009). The P400L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851667 SCV000899451 likely pathogenic Hereditary factor XI deficiency disease 2019-02-01 criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV000428449 SCV001715851 likely pathogenic not provided 2020-12-29 criteria provided, single submitter clinical testing PM1, PM2, PS4_moderate, PP3
Natera, Inc. RCV001273723 SCV001457105 likely pathogenic Plasma factor XI deficiency 2020-09-16 no assertion criteria provided clinical testing

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