ClinVar Miner

Submissions for variant NM_000128.3(F11):c.901T>C (p.Phe301Leu) (rs121965064)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000012667 SCV000678065 pathogenic Hereditary factor XI deficiency disease 2015-10-23 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727626 SCV000854901 pathogenic not provided 2018-04-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000012667 SCV000893673 likely pathogenic Hereditary factor XI deficiency disease 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000012667 SCV000448988 pathogenic Hereditary factor XI deficiency disease 2018-03-14 criteria provided, single submitter clinical testing The F11 c.901T>C (p.Phe301Leu) variant has been reported in at least four studies in seven individuals in a homozygous state, ten individuals in a compound heterozygous state, and was found in an additional 13 of 116 affected individuals of varied ethnicity in whom zygosity was not specified (Asakai et al. 1989; Asakai et al. 1991; Mitchell et al. 2006; Pike et al. 2016). All individuals had factor XI deficiency. The variant was also reported in a heterozygous state in six individuals who had factor XI activity ranging between 47% and 106%. The p.Phe301Leu variant has been found in two of 53 controls and is reported at a frequency of 0.00145 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies of transfected cells carrying the p.Phe301Leu variant showed significantly reduced expression of factor XI, but comparable clotting activity to wildtype (Meijers et al. 1992). Based on the collective evidence, the p.Phe301Leu variant is classified as pathogenic for factor XI deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000727626 SCV000949022 pathogenic not provided 2019-01-06 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 301 of the F11 protein (p.Phe301Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs121965064, ExAC 0.1%). This variant has been observed in numerous individuals and families affected with F11 deficiency and has been reported as an Ashkenazi Jewish founder mutation (PMID: 2813350, 19652879, 16835901, 2052060, 23929304). This variant is also known as Phe283Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 11892). Experimental studies have shown that this missense change results in reduced F11 secretion and impaired dimerization (PMID: 1547342, 15026311). For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000012667 SCV000899373 pathogenic Hereditary factor XI deficiency disease 2019-02-01 criteria provided, single submitter research
OMIM RCV000012667 SCV000032902 pathogenic Hereditary factor XI deficiency disease 1992-03-15 no assertion criteria provided literature only

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