Submissions for variant NM_000128.4(F11):c.1199C>T (p.Pro400Leu)

gnomAD frequency: 0.00001  dbSNP: rs533335580

Total submissions: 5

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
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000851667	SCV002515643	likely pathogenic	Hereditary factor XI deficiency disease		no assertion criteria provided	clinical testing