ClinVar Genomic variation as it relates to human health
NM_005141.5(FGB):c.794C>T (p.Pro265Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(1); Uncertain significance(6); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005141.5(FGB):c.794C>T (p.Pro265Leu)
Variation ID: 517313 Accession: VCV000517313.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q31.3 4: 154568456 (GRCh38) [ NCBI UCSC ] 4: 155489608 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 9, 2018 Apr 15, 2024 Feb 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005141.5:c.794C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005132.2:p.Pro265Leu missense NM_001184741.1:c.617C>T NP_001171670.1:p.Pro206Leu missense NC_000004.12:g.154568456C>T NC_000004.11:g.155489608C>T NG_008833.1:g.10477C>T LRG_558:g.10477C>T LRG_558t1:c.794C>T LRG_558p1:p.Pro265Leu - Protein change
- P265L, P206L
- Other names
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- Canonical SPDI
- NC_000004.12:154568455:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00100 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00243
Trans-Omics for Precision Medicine (TOPMed) 0.00248
The Genome Aggregation Database (gnomAD) 0.00275
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00315
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00100
The Genome Aggregation Database (gnomAD), exomes 0.00235
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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FGB | - | - |
GRCh38 GRCh37 |
192 | 223 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 12, 2024 | RCV000606613.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 1, 2017 | RCV000660563.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851949.1 | |
Likely benign (3) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000861598.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851887.1 | |
Uncertain significance (1) |
no assertion criteria provided
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May 1, 2020 | RCV001270563.1 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV002245051.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV002280881.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV003313786.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 7, 2023 | RCV003403425.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital afibrinogenemia
Affected status: unknown
Allele origin:
maternal
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782674.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Uncertain significance
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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Hypofibrinogenemia
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899936.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: male
Ethnicity/Population group: European
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Likely pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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Abnormal bleeding
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899370.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1: Observation 2:
Sex: male
Ethnicity/Population group: European
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Uncertain significance
(Mar 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731536.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. The p.Pro265Leu (NM _005141.4 c.794C>T) variant in FGB has been reported in 3 compound heterozygous and 1 … (more)
Variant classified as Uncertain Significance - Favor Benign. The p.Pro265Leu (NM _005141.4 c.794C>T) variant in FGB has been reported in 3 compound heterozygous and 1 homozygous individuals with Hypofibrinogenemia or Chronic thromboembolic p ulmonary hypertension (CTEPH), though the additional variants found in heterozyg osity were not well-established pathogenic variants (Brennan 2000 and Morris 200 9). In vitro functional studies provide conflicting data (Brennan 2000 and Morri s 2009). This variant has been identified in 0.381% (254/66716) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs52828882, rs2227436, rs6054) as well as 5% of controls in the Brennan 2000 study. In summary, the clinical significance of the p.Pro265Leu variant is uncertain; however, based on population frequency and functional data we favor a benign interpretation. (less)
Number of individuals with the variant: 1
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital afibrinogenemia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001310712.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Thrombus
Affected status: yes
Allele origin:
germline
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002569318.1
First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022 |
Clinical Features:
Recurrent thrombosis (present)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Familial dysfibrinogenemia
Affected status: yes
Allele origin:
germline
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV004013038.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Clinical Features:
hypodysfibrinogenemia (present)
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Uncertain significance
(May 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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FGB-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004104956.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The FGB c.794C>T variant is predicted to result in the amino acid substitution p.Pro265Leu. This variant is also described using legacy nomenclature as p.Pro235Leu, has … (more)
The FGB c.794C>T variant is predicted to result in the amino acid substitution p.Pro265Leu. This variant is also described using legacy nomenclature as p.Pro235Leu, has been reported in individuals with hypofibrinogenemia, chronic thromboembolic pulmonary hypertension or platelet defect (Brennan et al. 2000. PubMed ID: 10688828; Morris et al. 2009. PubMed ID: 19420351; Almazni et al. 2020. PubMed ID: 32935436). However, this variant has also been reported in healthy controls (Brennan et al. 2000. PubMed ID: 10688828). This variant is reported in 0.44% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-155489608-C-T). In ClinVar, this variant has conflicting interpretations of likely benign, uncertain significance, likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/517313/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely benign
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001001966.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Uncertain significance
(Feb 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003929391.2
First in ClinVar: Jun 03, 2023 Last updated: Apr 15, 2024 |
Comment:
Variant summary: FGB c.794C>T (p.Pro265Leu) results in a non-conservative amino acid change located in the C-terminal globular domain (IPR002181) of the encoded protein sequence. Four … (more)
Variant summary: FGB c.794C>T (p.Pro265Leu) results in a non-conservative amino acid change located in the C-terminal globular domain (IPR002181) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0043 in 1597176 control chromosomes, predominantly at a frequency of 0.0055 within the Non-Finnish European subpopulation in the gnomAD database (v4.0.0), including 17 homozygotes. Although this allele frequency is relatively high, however it is consistent with disease prevalence and penetrance estimates (PMID 29240685), allowing no clear conclusion about variant significance. The variant c.794C>T has been reported in several heterozygous individuals affected with hypofibrinogenemia and various (suspected) bleeding/coagulation disorders (e.g. Brennan_2000, Morris_2009, Downes_2019, Almazni_2020, Preisler_2020). Large scale population studies demonstrated an association with slightly lower (i.e. lower by ~10%) fibrinogen levels (Wassel_2010, Huffman_2015, de Vries_2016). In addition, at least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased clot formation and clot lysis in heterozygous patient samples, which corresponded to about 70% of the control values (Morris_2009). The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 32935436, 10688828, 33477601, 26105150, 19420351, 20978265, 26561523). ClinVar contains an entry for this variant (Variation ID: 517313). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(May 01, 2020)
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no assertion criteria provided
Method: research
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Thrombocytopenia
Abnormal bleeding
Affected status: yes
Allele origin:
germline
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Birmingham Platelet Group; University of Birmingham
Accession: SCV001450862.1
First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958214.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971599.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Afibrinogenemia
Affected status: yes
Allele origin:
unknown
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002515722.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Clinical Features:
Deep Vein Thrombosis (present) , Pulmonary Embolism (present) , low protein C (present)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a Large Cohort of Patients-A Single-Center Experience in Genetic Diagnosis. | Preisler B | Journal of clinical medicine | 2021 | PMID: 33477601 |
A comprehensive bioinformatic analysis of 126 patients with an inherited platelet disorder to identify both sequence and copy number genetic variants. | Almazni I | Human mutation | 2020 | PMID: 32935436 |
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. | de Vries PS | Human molecular genetics | 2016 | PMID: 26561523 |
Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. | Huffman JE | Blood | 2015 | PMID: 26105150 |
Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe). | Wassel CL | Blood | 2011 | PMID: 20978265 |
High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension. | Morris TA | Blood | 2009 | PMID: 19420351 |
Hypofibrinogenemia in an individual with 2 coding (gamma82 A-->G and Bbeta235 P-->L) and 2 noncoding mutations. | Brennan SO | Blood | 2000 | PMID: 10688828 |
Text-mined citations for rs6054 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.