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EVC2
EvC ciliary complex subunit 2
The EVC2 gene provides instructions for a protein important for normal growth and development, particularly affecting bones, teeth, and heart structures, and is implicated in Ellis-van Creveld syndrome. EVC2 encodes a protein that plays a role in the primary cilia, microscopic structures involved in cellular signalling pathways crucial for development.
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, or EvC ciliary complex subunit 2, is involved in producing a protein essential for typical growth and development. This protein is especially important for the formation of bones and teeth. The EVC2 gene is closely located to the EVC gene on chromosome 4, and these two genes are thought to have coordinated functions, potentially forming a functional complex.
What the gene does
The protein produced from the EVC2 gene is found within primary cilia, which are small, finger-like projections extending from cell surfaces. These cilia act as crucial cellular antennae, mediating signalling pathways that transmit information between cells. The EVC2 protein is believed to help regulate the Sonic Hedgehog signalling pathway, which is vital for cell growth, cell specialisation, and the patterning of many body parts during development. While its precise function is still being investigated, its localisation within primary cilia suggests a key role in ciliary-mediated signalling processes influencing skeletal and other developmental pathways.
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Chromosome location
The EVC2 gene is situated on chromosome 4 at position 4p16.2. It is found in close proximity to the EVC gene, and both genes are often considered together due to their functional relationship. The EVC2 gene spans a genomic region that includes its coding sequences.
Protein structure
The EVC2 protein consists of 1308 amino acids. Its structural organisation includes several distinct regions. There is a Disordered region found between amino acids 36-76 and another between amino acids 784-816. The protein also contains multiple Coiled coil domains, located at amino acids 455-578, 636-800, and 1001-1113. These coiled-coil structures often facilitate protein-protein interactions.
Key variants
Variants in the EVC2 gene can alter the protein's function, leading to various health outcomes. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions within the gene. Over 30 different pathogenic variants in EVC2 have been identified, particularly those associated with specific inherited conditions. The clinical impact of a variant depends on its nature and location within the gene.
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.1939_1945del | p.Thr647fs | Pathogenic | ★★☆☆ | Ellis-van Creveld syndrome |
c.2041C>T | p.Gln681Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Curry-Hall syndrome |
c.2581C>T | p.Gln861Ter | 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.329dup | p.Ile111fs | 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 primarily associated with inherited conditions that affect development. The most well-known condition linked to EVC2 is Ellis-van Creveld syndrome, an autosomal recessive disorder characterised by features such as dwarfism, abnormalities of the nails and teeth, and cardiac defects. Another condition, Weyers acrofacial dysostosis, which presents with milder symptoms affecting teeth, nails, and bones, is also associated with EVC2 variants, typically inherited in an autosomal dominant pattern.
Inheritance pattern
Conditions caused by pathogenic EVC2 variants typically follow autosomal recessive or autosomal dominant inheritance.
Carrier frequency by population How common is heterozygous EVC2 carrier status across ancestry groups?UK clinical status
The EVC2 gene is included in several UK NHS national genomic testing panels, indicating its clinical significance within the UK healthcare system. It is listed as 'green' on PanelApp for conditions such as DDG2P (developmental disorders), Foetal anomalies (R21), Neurological ciliopathies, Rare multisystem ciliopathy disorders, Skeletal ciliopathies, Skeletal dysplasia (R104), and Thoracic dystrophies, meaning there is strong evidence for its association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the EVC2 gene?
The EVC2 gene provides instructions for making a protein found in primary cilia. This protein is believed to regulate the Sonic Hedgehog signalling pathway, which is critical for cell growth, specialisation, and the proper development of various body parts, particularly bones and teeth.
What health conditions are associated with variants in the EVC2 gene?
Variants in the EVC2 gene are primarily associated with Ellis-van Creveld syndrome, an inherited disorder causing dwarfism, dental and nail abnormalities, and heart defects. It is also linked to Weyers acrofacial dysostosis, a milder condition affecting teeth, nails, and bones.
How is Ellis-van Creveld syndrome inherited?
Ellis-van Creveld syndrome caused by EVC2 variants is typically inherited in an autosomal recessive manner. This means an individual must inherit two altered copies of the EVC2 gene, one from each parent, to develop the condition. Parents who carry one altered copy are generally unaffected but are carriers.
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