ClinVar Genomic variation as it relates to human health

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 301 of the F11 protein (p.Phe301Leu). This variant is present in population databases (rs121965064, gnomAD 2.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with F11 deficiency (PMID: 2052060, 2813350, 16835901, 19652879, 23929304). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 2052060, 2813350, 16835901, 19652879, 23929304). This variant is also known as p.Phe283Leu. ClinVar contains an entry for this variant (Variation ID: 11892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt F11 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects F11 function (PMID: 1547342, 15026311). For these reasons, this variant has been classified as Pathogenic.

Common variant in the Ashkenazi Jewish population, observed multiple times with a pathogenic variant on the opposite allele (in trans) or in the homozygous state in unrelated patients in published literature with factor XI deficiency (PMID: 2813350, 19652879); Reported as a single heterozygous variant in two individuals with Factor XI deficiency, one of whom was also noted to have Factor VIII deficiency (PMID: 19652879); Published functional studies demonstrate impaired dimer formation resulting in decreased factor XI secretion (PMID: 15026311, 18024374); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as F283L and Type III mutation; This variant is associated with the following publications: (PMID: 9787168, 11564078, 18839438, 23332144, 16086308, 21668437, 22016685, 31064749, 1547342, 22975760, 25333069, 2813350, 26558335, 17384215, 22159456, 25158988, 16835901, 24982842, 19347998, 15140127, 18024374, 18515884, 29178608, 30487145, 31447099, 31980526, 34570182, 31589614, 19652879, 15026311)

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.

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.

PP1, PP3, PP4, PP5, PM1, PM3, PS3

The F11 c.901T>C (p.Phe301Leu) variant, also reported as Phe283Leu when numbered from the mature protein, has been reported in the heterozygous, compound heterozygous, and homozygous state in multiple individuals with factor XI deficiency (Asakai R et al., PMID: 2813350; Asakai R et al., PMID: 2052060; Mitchell M et al., PMID: 16835901; Pike GN et al., PMID: 26558335). Individuals who are heterozygous for this variant experience partial factor XI deficiency, while individuals who are compound heterozygous or homozygous for this variant experience severe factor XI deficiency. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 2.4% in the Ashkenazi Jewish population, which is consistent with the frequency of partial factor XI deficiency in that population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to factor XI function. In support of this prediction, studies of transfected cells carrying the p.Phe301Leu variant showed significantly reduced expression of factor XI, but comparable clotting activity to wildtype (Meijers JC et al., PMID: 1547342). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

F11: PM3:Very Strong, PM2

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with factor XI deficiency. Dominant missense variants have been shown to have a dominant negative disease mechanism (PMID:15026311), whilst loss of function variants are generally recessive, though symptomatic carriers have been reported (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Individuals with biallelic variants generally have a more severe phenotype. Heterozygous individuals may be asymptomatic despite having FXI deficiency (PMID:18446632). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a high degree of variable expression, with intrafamilial variation reported (PMID: 32118380). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v4) >=0.001 and <0.01 for a dominant condition (959 heterozygotes, 8 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated APPLE 4 domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a well reported pathogenic variant (also known as F283L) that has been shown to cause type III Factor XI deficiency. It is a founder mutation in the Ashkenazi Jewish population (ClinVar, PMID: 16835901). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The F11 c.901T>C variant is predicted to result in the amino acid substitution p.Phe301Leu. This variant, previously reported as p.Phe283Leu, has been reported to be causative for hemophilia C in both autosomal dominant and recessive forms of the disease (Asakai et al. 1989. PubMed ID: 2813350; Kravtsov et al. 2004. PubMed ID: 15026311; Mitchell et al. 2006. PubMed ID: 16835901). This variant is reported in 2.4% of alleles in individuals of Ashkenazi Jewish descent and includes five homozygotes in gnomAD. This variant is interpreted as pathogenic.

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.

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.