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FANCG
FA complementation group G
The FANCG gene provides instructions for a protein critical to the Fanconi Anaemia pathway, which is essential for repairing specific types of DNA damage. The FANCG gene encodes a protein that forms part of the FA core complex, playing a vital role in the body's response to DNA damage, particularly interstrand cross-links.
FANCG is located on the short (p) arm of chromosome 9, at band 9p13.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The FANCG gene provides the blueprint for a protein integral to the Fanconi Anaemia (FA) pathway [PMID:30177740], a cellular mechanism involved in maintaining genomic stability. This pathway activates when DNA replication is interrupted by certain types of damage, specifically interstrand cross-links (ICLs). The FANCG protein, along with several others, helps to coordinate the repair of these challenging DNA lesions, which can otherwise impede cell division and lead to cellular dysfunction [PMID:17924330].
What the gene does
The FANCG protein is a key component of the FA core complex, a multi-protein assembly responsible for initiating DNA repair within the Fanconi Anaemia pathway. When DNA replication encounters interstrand cross-links (ICLs), the FA core complex is activated. This complex comprises eight FA proteins, including FANCG, and two associated proteins. It modifies two other proteins, FANCD2 and FANCI, through a process called monoubiquitination [PMID:17924330]. This modification acts as a signal, recruiting other DNA repair proteins to the site of damage, allowing the ICLs to be resolved and enabling DNA replication to continue. These cross-links are abnormal connections between opposite DNA strands and can arise from endogenous toxins or certain cancer treatments [PMID:28757457].
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Chromosome location
The FANCG gene is located on the short (p) arm of chromosome 9, specifically at position 13.3. This precise genomic address helps in mapping the gene and understanding its inheritance patterns.
Protein structure
The FANCG protein consists of 622 amino acids. Its structure includes specific domains crucial for its function. These are the TPR 1 (Repeat) domain spanning amino acids 246-279, followed by TPR 2 (Repeat) from amino acids 344-377, TPR 3 (Repeat) from amino acids 453-486, and TPR 4 (Repeat) located between amino acids 514-547. These domains are typically involved in protein-protein interactions within the FA core complex.
Key variants
Genetic variations, or variants, in the FANCG gene can alter the protein's structure or function, potentially impairing its role in DNA repair. These changes can range from single nucleotide substitutions to larger deletions or insertions, and their impact on the protein's activity can vary significantly. Understanding these variants is crucial for assessing their potential clinical implications.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1133C>A | p.Ser378Ter | Pathogenic | ★★☆☆ | Fanconi anemia |
c.1341C>G | p.Tyr447Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.1473del | p.Glu492fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group G |
c.601_602del | p.Gln201fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.601C>T | p.Gln201Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.684del | p.Ala228_Leu229insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group G |
c.692del | p.Ser231fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.694_695del | p.Leu232fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.787_788del | p.Gln263fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.836G>A | p.Trp279Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the FANCG gene are strongly associated with Fanconi Anaemia [PMID:30177740], an inherited disorder characterised by a decrease in bone marrow function, an increased risk of developing certain cancers, and various physical differences. Pathogenic variants in FANCG represent one of several genetic causes of Fanconi Anaemia. This condition typically leads to reduced production of blood cells.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic FANCG variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The FANCG gene is included in several NHS England Genomic Medicine Service approved panels for both rare diseases and cancer susceptibility. It is assessed under panels such as Adult solid tumours cancer susceptibility, Childhood solid tumours, Confirmed Fanconi Anaemia or Bloom syndrome, Cytopenias and congenital anaemias, and Foetal anomalies. Furthermore, it is listed in the DDG2P (Deciphering Developmental Disorders) database.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the FANCG gene?
The FANCG gene is vital for producing a protein that is part of the Fanconi Anaemia (FA) pathway, which is a key cellular mechanism for repairing specific types of DNA damage, particularly interstrand cross-links.
What medical condition is associated with FANCG gene variants?
Pathogenic variants in the FANCG gene are primarily associated with Fanconi Anaemia, an inherited disorder characterised by bone marrow failure, an elevated cancer risk, and specific physical features.
How does the FANCG protein contribute to DNA repair?
The FANCG protein is a subunit of the FA core complex. This complex activates other proteins, FANCD2 and FANCI, by attaching ubiquitin molecules to them, which then recruits DNA repair proteins to fix interstrand cross-links.
References
- Kitao H, Takata M. Fanconi anemia: a disorder defective in the DNA damage response. International journal of hematology. 2011. PMID: 21331524
- Deakyne JS, Mazin AV. Fanconi anemia: at the crossroads of DNA repair. Biochemistry. Biokhimiia. 2011. PMID: 21568838
- Kee Y, D'Andrea AD. Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes & development. 2010. PMID: 20713514
- de Winter JP, Joenje H. The genetic and molecular basis of Fanconi anemia. Mutation research. 2009. PMID: 19061902
- Taniguchi T, D'Andrea AD. Molecular pathogenesis of Fanconi anemia: recent progress. Blood. 2006. PMID: 16493006
- Mathew CG. Fanconi anaemia genes and susceptibility to cancer. Oncogene. 2006. PMID: 16998502