ClinVar Miner

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

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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
NIHR Bioresource Rare Diseases, University of Cambridge RCV000012667 SCV000899373 pathogenic Hereditary factor XI deficiency disease 2019-02-01 criteria provided, single submitter research
Invitae RCV000727626 SCV000949022 pathogenic not provided 2020-10-27 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258090 SCV001434933 pathogenic Factor XI 2018-08-13 criteria provided, single submitter clinical testing This c.901T>C (p.Phe301Leu) variant in the F11 gene has been reported in multiple patients with XI deficiency (PMID 2813350, 16835901, 26558335). This variant is observed in the 2.4% of Ashkenazi Jewish population and 4 times homozygous all from Ashkenazi Jewish population in the gnomAD database, while extremely rare in the other ethnic groups. In vitro assays showed that the mutant protein is secreted at a reduced level (8% of wild type) due to a defect in dimerization of the protein [PMID 1547342]. Phenylalanine at amino acid position 301 of the F11 protein is conserved in mammals. Computer-based algorithms predict this p.Phe301Leu change to be deleterious.This variant is thus classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000727626 SCV001715850 pathogenic not provided 2020-09-02 criteria provided, single submitter clinical testing PS3, PM1, PM3, PP1, PP3, PP4, PP5
OMIM RCV000012667 SCV000032902 pathogenic Hereditary factor XI deficiency disease 1992-03-15 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000012667 SCV001142343 pathogenic Hereditary factor XI deficiency disease 2020-01-06 no assertion criteria provided curation NM_000128.3:c.901T>C in the F11 gene has an allele frequency of 0.024 in Ashkenazi Jewish subpopulation in the gnomAD database. The F11 c.901T>C (p.Phe301Leu) variant, also known as F283L in literatures, has been reported in individuals with factor XI deficiency in homozygous state and compound heterozygous states with p.E135X (PMID: 26558335; 2813350; 16835901). All individuals had factor XI deficiency. Experimental studies have shown that this missense change results in reduced F11 secretion and impaired dimerization (PMID: 1547342).Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000012667 SCV001450569 pathogenic Hereditary factor XI deficiency disease no assertion criteria provided clinical testing The F11 p.F301L variant has been reported in multiple individuals with factor XI deficiency and is an Ashkenazi Jewish founder mutation, reported to account for 47% of Ashkenazi Jewish factor XI deficiency mutant alleles in one study (Asakai_1989_PMID:2813350; Asakai_1991_PMID:2052060; Mitchell_2006_PMID:16835901). The variant was identified in dbSNP (ID: rs121965064), ClinVar (classified as pathogenic by Counsyl, EGL Genetics, Illumina and Invitae, and as likely pathogenic by Fulgent Genetics) and LOVD 3.0 (classified as pathogenic and likely pathogenic). The variant was identified in control databases in 297 of 282824 chromosomes (5 homozygous) at a frequency of 0.00105 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 247 of 10368 chromosomes (freq: 0.02382), Other in 13 of 7226 chromosomes (freq: 0.001799), European (non-Finnish) in 33 of 129144 chromosomes (freq: 0.000256) and Latino in 4 of 35438 chromosomes (freq: 0.000113), but was not observed in the African, East Asian, European (Finnish), or South Asian populations. The p.Phe301 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional expression of the p.F301L mutant human factor XI protein demonstrated impaired dimerization leading reduced secretion compared to wildtype (Meijers_1992_PMID:1547342). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Natera, Inc. RCV001273722 SCV001457104 pathogenic Plasma factor XI deficiency 2020-09-16 no assertion criteria provided clinical testing

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