NM_000128.4(F11):c.403G>T (p.Glu135Ter) AND Hereditary factor XI deficiency disease

Germline classification:: Pathogenic (14 submissions)
Last evaluated:: Mar 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000012666.49

Allele description [Variation Report for NM_000128.4(F11):c.403G>T (p.Glu135Ter)]

NM_000128.4(F11):c.403G>T (p.Glu135Ter)

Gene:

F11:coagulation factor XI [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q35.2

Genomic location:

Preferred name:

NM_000128.4(F11):c.403G>T (p.Glu135Ter)

Other names:

F11, GLU117TER; E117*; E117X; p.Glu135*

HGVS:

NC_000004.12:g.186274193G>T
NG_008051.1:g.13230G>T
NM_000128.4:c.403G>TMANE SELECT
NM_001354804.2:c.403G>T
NP_000119.1:p.Glu135Ter
NP_000119.1:p.Glu135Ter
NP_001341733.1:p.Glu135Ter
LRG_583t1:c.403G>T
LRG_583:g.13230G>T
LRG_583p1:p.Glu135Ter
NC_000004.11:g.187195347G>T
NM_000128.3:c.403G>T
NM_000128.4:c.403G>T
c.403G>T (p.Glu135*)

Protein change:

E135*; GLU117TER

Links:

OMIM: 264900.0002; dbSNP: rs121965063

NCBI 1000 Genomes Browser:

rs121965063

Molecular consequence:

NM_000128.4:c.403G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354804.2:c.403G>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Hereditary factor XI deficiency disease
Synonyms:: Plasma thromboplastin antecedent deficiency; PTA deficiency; Rosenthal syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012897; MeSH: D005173; MedGen: C0015523; Orphanet: 329; OMIM: 612416

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000032901	OMIM	no assertion criteria provided	Pathogenic (Jul 18, 1991)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 2813350, 2052060
SCV000448983	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16835901, 2813350, 15140127, 2052060 ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000678061	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Oct 26, 2015)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 2813350, 15026311, 2052060, 10593931 Citation Link,
SCV000839954	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 5, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000893671	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000899337	NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2019)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31064749
SCV001142342	Reproductive Health Research and Development, BGI Genomics	no assertion criteria provided	Pathogenic (Jan 6, 2020)	germline	curation
SCV001365779	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 31, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15140127, 16835901, 2052060, 24033266
SCV002022262	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002500851	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002519640	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV002570361	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 4, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15140127, 16835901, 9326232, 25741868
SCV004099401	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Pathogenic (Oct 30, 2023)	germline	clinical testing
SCV004807525	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	yes	1	not provided	not provided	1	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
European	unknown	yes	7	not provided	not provided	7	not provided	research

Citations

PubMed

Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations.

Asakai R, Chung DW, Ratnoff OD, Davie EW.

Proc Natl Acad Sci U S A. 1989 Oct;86(20):7667-71.

PubMed [citation]

PMID:: 2813350
PMCID:: PMC298131

Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain.

Kravtsov DV, Wu W, Meijers JC, Sun MF, Blinder MA, Dang TP, Wang H, Gailani D.

Blood. 2004 Jul 1;104(1):128-34. Epub 2004 Mar 16.

PubMed [citation]

PMID:: 15026311

See all PubMed Citations (10)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000032901.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 4 Ashkenazi Jewish patients with factor XI deficiency (612416), Asakai et al. (1989) identified compound heterozygosity for 2 mutations in the F11 gene: a G-to-T transversion in exon 5, resulting in a glu117-to-ter (E117X) substitution, and a T-to-C transition in exon 9, resulting in a phe283-to-leu substitution (F283L; 264900.0003). In another Ashkenazi Jewish patient, they identified compound heterozygosity for the E117X mutation and a splice site mutation (264900.0001).

This variant is found in Iraqi Jews, among whom factor XI deficiency is rare. Asakai et al. (1991) found this mutation in 49% of 86 alleles examined from Ashkenazi Jews in Israel.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000448983.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000678061.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839954.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893671.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics, SCV000899337.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)
2	European	1	not provided	not provided	research	PubMed (2)
3	European	1	not provided	not provided	research	PubMed (2)
4	European	1	not provided	not provided	research	PubMed (2)
5	European	1	not provided	not provided	research	PubMed (2)
6	European	1	not provided	not provided	research	PubMed (2)
7	European	1	not provided	not provided	research	PubMed (2)
8	European	1	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
7	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
8	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Reproductive Health Research and Development, BGI Genomics, SCV001142342.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365779.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	1	not provided

From Revvity Omics, Revvity, SCV002022262.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology, SCV002500851.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Mendelics, SCV002519640.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV002570361.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004099401.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004807525.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

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