Submissions for variant NM_005141.5(FGB):c.794C>T (p.Pro265Leu)

gnomAD frequency: 0.00278  dbSNP: rs6054

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000606613	SCV000731536	uncertain significance	not specified	2017-03-28	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000660563	SCV000782674	pathogenic	Congenital afibrinogenemia	2017-06-01	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851949	SCV000899370	likely pathogenic	Abnormal bleeding	2019-02-01	criteria provided, single submitter	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851887	SCV000899936	uncertain significance	Hypofibrinogenemia	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000861598	SCV001001966	likely benign	not provided	2025-01-26	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002280881	SCV002569318	uncertain significance	Thrombus		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000606613	SCV003929391	likely benign	not specified	2025-01-20	criteria provided, single submitter	clinical testing	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 0.0024 in 251290 control chromosomes, predominantly at a frequency of 0.0044 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in FGB causing Afibrinogenemia, Congenital phenotype. c.794C>T has been reported in several heterozygous individuals affected with hypofibrinogenemia and various (suspected) bleeding/coagulation disorders (Brennan_2000, Morris_2009, Downes_2019, Almazni_2020, Preisler_2020). Large scale population studies demonstrated an association with slightly lower (~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 likely benign.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV003313786	SCV004013038	uncertain significance	Familial dysfibrinogenemia		criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000660563	SCV006055040	uncertain significance	Congenital afibrinogenemia	2023-08-18	criteria provided, single submitter	research
Birmingham Platelet Group; University of Birmingham	RCV001270563	SCV001450862	uncertain significance	Abnormal bleeding; Thrombocytopenia	2020-05-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000861598	SCV001958214	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000861598	SCV001971599	uncertain significance	not provided		no assertion criteria provided	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002245051	SCV002515722	uncertain significance	Afibrinogenemia		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003403425	SCV004104956	uncertain significance	FGB-related disorder	2024-06-17	no assertion criteria provided	clinical testing	The FGB c.794C>T variant is predicted to result in the amino acid substitution p.Pro265Leu. This variant, 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. 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.