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EVC2
EvC ciliary complex subunit 2
The EVC2 gene provides instructions for a protein crucial for normal growth and development, particularly for bones and teeth, and is associated with conditions like Ellis-van Creveld syndrome. EVC2, or EvC ciliary complex subunit 2, encodes a protein found in primary cilia, which are cellular projections involved in signalling.
EVC2 is located on the short (p) arm of chromosome 4, at band 4p16.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The EVC2 gene, also known as EvC ciliary complex subunit 2, is fundamental for proper human growth and development. It provides the genetic blueprint for a protein that is located within primary cilia, which are microscopic, finger-like structures on cell surfaces that facilitate cell-to-cell communication. Disruptions in the EVC2 gene are linked to inherited conditions affecting bone and tooth development, such as Ellis-van Creveld syndrome.
What the gene does
The EVC2 protein is localised to primary cilia, which are critical for various cellular signalling pathways. While its precise molecular function is still under investigation, the EVC2 protein is understood to be involved in regulating the Sonic Hedgehog signalling pathway. This pathway is a fundamental regulator of cell growth, differentiation, and the patterning of many body structures during embryonic development. The EVC2 protein's contribution to this pathway highlights its importance in the coordinated development of tissues, particularly bones and teeth. The EVC2 gene is located very close to the EVC gene on chromosome 4, and it is thought that these two genes may have related functions and coordinated activity.
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Chromosome location
The EVC2 gene is situated on the short arm of chromosome 4 at position 16.2, denoted as 4p16.2. This specific genomic location places EVC2 within a region known to harbour genes involved in developmental processes.
Protein structure
The EVC2 protein consists of 1308 amino acids and features several distinct structural elements. It contains multiple coiled-coil domains, which are typically involved in protein-protein interactions; these are found at amino acids 455-578, 636-800, and 1001-1113. Additionally, the protein includes two disordered regions, located at amino acids 36-76 and 784-816, which may contribute to its flexibility and adaptability in binding other molecules.
Key variants
Genetic variations within the EVC2 gene can impact its function, leading to a spectrum of health conditions. These variants include changes in the DNA sequence that can result in an altered protein, or in some cases, a prematurely truncated, non-functional protein. The clinical presentation often depends on the specific nature of the variant and whether one or both copies of the gene are affected.
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.2041C>T | p.Gln681Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Curry-Hall syndrome |
c.2856_2857del | p.Arg952fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ellis-van Creveld syndrome |
c.2881G>T | p.Gly961Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Curry-Hall syndrome |
c.2893C>T | p.Gln965Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Curry-Hall syndrome |
c.2944_2945del | p.Leu982fs | Pathogenic | ★★☆☆ | Curry-Hall syndrome |
c.2989G>T | p.Glu997Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ellis-van Creveld syndrome |
c.30dup | p.Thr11fs | Pathogenic/Likely pathogenic | ★★☆☆ | Curry-Hall syndrome |
c.3374dup | p.Ser1126fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ellis-van Creveld syndrome |
c.449del | p.Leu150fs | Pathogenic/Likely pathogenic | ★★☆☆ | Curry-Hall syndrome |
c.816+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Ellis-van Creveld syndrome |
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
Pathogenic variants in the EVC2 gene are associated with several inherited conditions, primarily affecting skeletal and dental development. The most well-known condition linked to EVC2 is Ellis-van Creveld syndrome, which typically presents with short stature, abnormal nails and teeth, and heart defects. Another related condition is Weyers acrofacial dysostosis, which shares similar, but generally milder, symptoms.
Inheritance pattern
Conditions caused by pathogenic EVC2 variants typically follow ar/ad 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 EVC2 gene is recognised within the UK's National Health Service (NHS) Genomic Medicine Service. It is listed as 'green' on several NHS Genomic Medicine Service national panels via PanelApp, indicating strong evidence for its association with specific conditions. These include panels for DDG2P, Foetal anomalies (R21), Neurological ciliopathies, Rare multisystem ciliopathy disorders, Skeletal ciliopathies, Skeletal dysplasia (R104), and Thoracic dystrophies.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the EVC2 gene?
The EVC2 gene, or EvC ciliary complex subunit 2, provides instructions for making a protein found in primary cilia. This protein is important for normal growth and development, particularly for bones and teeth, by helping to regulate cell signalling pathways.
What conditions are associated with EVC2 gene variants?
Variants in the EVC2 gene are primarily associated with Ellis-van Creveld syndrome, an inherited disorder characterised by short stature, abnormal nails and teeth, and heart defects. It is also linked to Weyers acrofacial dysostosis, which has similar but typically milder symptoms.
How does the EVC2 protein function in the body?
The EVC2 protein is located in primary cilia, which are cell structures involved in transmitting signals between cells. It is thought to help regulate the Sonic Hedgehog signalling pathway, crucial for cell growth, specialisation, and the proper formation of many body parts during development.
References
- Dorn KV, Hughes CE, Rohatgi R. A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Developmental cell. 2012. PMID: 22981989
- Blair HJ, Tompson S, Liu YN. Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus. BMC biology. 2011. PMID: 21356043
- Sund KL, Roelker S, Ramachandran V. Analysis of Ellis van Creveld syndrome gene products: implications for cardiovascular development and disease. Human molecular genetics. 2009. PMID: 19251731
- Valencia M, Lapunzina P, Lim D. Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling. Human mutation. 2009. PMID: 19810119
- Ruiz-Perez VL, Goodship JA. Ellis-van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to hedgehog ligands. American journal of medical genetics. Part C, Seminars in medical genetics. 2009. PMID: 19876929
- Tompson SW, Ruiz-Perez VL, Blair HJ. Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients. Human genetics. 2007. PMID: 17024374
- Ye X, Song G, Fan M. A novel heterozygous deletion in the EVC2 gene causes Weyers acrofacial dysostosis. Human genetics. 2006. PMID: 16404586
- Ruiz-Perez VL, Tompson SW, Blair HJ. Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. American journal of human genetics. 2003. PMID: 12571802
- Galdzicka M, Patnala S, Hirshman MG. A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. Molecular genetics and metabolism. 2002. PMID: 12468274
- Morrell CH, Brant LJ. Modelling hearing thresholds in the elderly. Statistics in medicine. 1991. PMID: 1925173