ClinVar Miner

Submissions for variant NM_000128.3(F11):c.403G>T (p.Glu135Ter) (rs121965063)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000311271 SCV000330013 pathogenic not provided 2018-06-17 criteria provided, single submitter clinical testing The E135X variant in the F11 gene has been identified in the heterozygous state, homozygous state, and compound heterozygous state in individuals with Factor XI deficiency in published literature; reported as E117X due to alternate nomenclature (Asaki et al., 1989; Mitchell et al., 2006). Additionally, studies in a fibroblast cell line with the E135X variant show that this variant impacts the function of the protein (Kravtsov et al., 2004). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E135X variant is observed in 241/277028 (0.088%) total alleles, including 3 unrelated homozygous individuals in large population cohorts (Lek et al., 2016). We interpret E135X as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000012666 SCV000448983 pathogenic Hereditary factor XI deficiency disease 2016-06-14 criteria provided, single submitter clinical testing The c.403G>T (p.Glu135Ter) stop-gained variant is a founder variant in the Ashkenazi Jewish population predicted to result in premature termination of the protein. The p.Glu135Ter variant has been reported in three studies and is found in a total of 28 factor XI deficiency patients including seven homozygotes, eight compound heterozygotes, and 13 heterozygotes (Asakai et al. 1989; Bolton-Maggs et al. 2004; Mitchell et al. 2006). Control data are unavailable for this variant, which is reported at a frequency of 0.00128 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Glu135Ter variant is classified as pathogenic for factor XI deficiency.
Counsyl RCV000012666 SCV000678061 pathogenic Hereditary factor XI deficiency disease 2015-10-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000311271 SCV000700670 pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000012666 SCV000839954 pathogenic Hereditary factor XI deficiency disease 2017-06-05 criteria provided, single submitter clinical testing This c.403G>T (p.Glu135*) variant in the F11 gene was first reported in 5 compound heterozygous patients with F11 deficiency [reported as p.Glu117*, Type II mutation, in PMID 2813350]. The patients had none to moderate bleeding symptoms. This variant was also reported in 3 homozygous and 3 compound heterozygous patients of Jewish descent with F11 deficiency [PMID 15140127]. This c.403G>T variant encodes for a nonsense codon in exon 5 and creates a stop codon at amino acid position 135 of the F11 protein. This variant has been detected in 95 heterozygous and one homozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/4-187195347-G-T). This variant is thus classified as pathogenic. <BR>Apparent homozygosity of this variant may be caused by the presence of the mutant allele on both alleles of this individual, or the presence of a mutant allele on one allele and an exonic deletion on the opposite allele. Copy number variant (CNV) analysis or segregation analysis is necessary to assess the apparent homozygosity status of this variant.
Fulgent Genetics,Fulgent Genetics RCV000012666 SCV000893671 pathogenic Hereditary factor XI deficiency disease 2018-10-31 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000012666 SCV000899337 pathogenic Hereditary factor XI deficiency disease 2019-02-01 criteria provided, single submitter research
Invitae RCV000311271 SCV000947700 pathogenic not provided 2020-10-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu135*) in the F11 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121965063, ExAC 0.1%). This variant has been reported in many individuals with Factor XI deficiency (PMID: 2813350, 15026311). In the literature, this variant is also known as p.Glu117Stop. ClinVar contains an entry for this variant (Variation ID: 11891). Loss-of-function variants in F11 are known to be pathogenic (PMID: 15728123, 23929304, 25074526). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000012666 SCV001365779 pathogenic Hereditary factor XI deficiency disease 2020-03-31 criteria provided, single submitter clinical testing The p.Glu135X (also known as p.Glu117X) variant in F11 has been reported in in the homozygous or compound heterozygous state in >40 individuals with factor XI deficiency and is a founder mutation in the Ashkenazi Jewish population (Asakai 1991, Bolton-Maggs 2004, Mitchell 2006). This variant has also been reported in ClinVar (Variation ID 11891) and has been identified in 1.7% (177/10364) of Ashkenazi Jewish chromosomes by gnomAD, including 3 homozygotes (http://gnomad.broadinstitute.org). However, this frequency is consistent with a recessive carrier frequency for a known founder variant. Functional studies support an impact on protein function (Asakai 1991). This nonsense variant leads to a premature termination codon at position 135, which is predicted to lead to a truncated or absent protein. Loss of function of the F11 gene is an established disease mechanism in autosomal recessive factor XI deficiency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive factor XI deficiency. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1, PS3_Supporting.
Ambry Genetics RCV001266322 SCV001444495 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000311271 SCV001500791 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing
OMIM RCV000012666 SCV000032901 pathogenic Hereditary factor XI deficiency disease 1991-07-18 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000012666 SCV001142342 pathogenic Hereditary factor XI deficiency disease 2020-01-06 no assertion criteria provided curation NM_000128.3:c.403G>T in the F11 gene has an allele frequency of 0.017 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.403G>T (p.Glu135Ter) stop-gained variant is a founder variant in the Ashkenazi Jewish population predicted to result in premature termination of the protein. The p.Glu135Ter variant has been reported in factor XI deficiency patients, compound heterozygotes with p.Q251X and p.F301L (also known as F283L) (PMID: 15140127; 16835901). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4.
Birmingham Platelet Group; University of Birmingham RCV001270535 SCV001450834 pathogenic Abnormal bleeding; Thrombocytopenia 2020-05-01 no assertion criteria provided research
Natera, Inc. RCV001273717 SCV001457099 pathogenic Plasma factor XI deficiency 2020-09-16 no assertion criteria provided clinical testing

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