EVC

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: ClinGen

The *EVC* gene is located on chromosome 4 at 4p16.2 and encodes the EvC ciliary complex subunit 1. The protein encodes a 992-amino acid protein with a transmembrane domain, 3 nuclear localization signals, and a leucine zipper motif. This protein creates a complex with *EVC2* and is located at the base of the primary cilia to regulate Hedgehog signaling. This *EVC-EVC2* complex is involved in endochondral growth and skeletal development. *EVC* has been shown to be expressed in human embryonic tissue within the developing bone, heart, kidney, and lung (Ruiz-Perez et al., PMID: 10700184). Multiple disease entities have been reported in association with this gene, including autosomal recessive Ellis-van Creveld syndrome and autosomal dominant Weyers acrofacial dysostosis (WAD). Patients with biallelic *EVC* gene variants have been reported to have features involving short stature and limbs, postaxial polydactyly, dysplastic nails, congenital heart defects, atrial septation, and genitourinary anomalies. Affected individuals may have dental anomalies similar to acrofacial dysostosis. One case reported by Ruiz-Perez et al. (2000) noted that a child with compound heterozygous variants in *EVC* and features of Ellis-van Creveld syndrome, had one parent clinically described as having features of WAD with a heterozygous *EVC* variant. There are no additional cases describing an individual with a heterozygous *EVC* variant being affected. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in the molecular mechanism, inheritance pattern, or phenotypic spectrum. Therefore, these disease entities have been lumped into one disease entity: autosomal recessive Ellis-van Creveld syndrome: MONDO:0009162. The *EVC* gene was first reported in relation to autosomal recessive Ellis-van Creveld syndrome in 1964 (McKusick et al., PMID: 14217223). At least 30 variants (nonsense, frameshift, missense, splice site) have been reported in 28 probands across 3 publications (PMIDs: 10700184, 23220543, 34930662). The mechanism of pathogenicity is known to be loss of function. A maximum score of 12 points for genetic evidence was reached, considering case-level data and segregation data. The literature contains additional case reports. This gene-disease relationship is also supported by expression studies and animal models. The scored expression data include the detection of cloned *EVC* in human embryonic bone, heart, kidney, and lung in human embryonic tissue at Carnegie stages 19 and 21 (Ruiz et al., PMID: 10700184). In addition, another expression study noted cloned mouse *EVC* being expressed strongest in the secondary heart field (Sund et al., PMID: 19251731). A mouse model for Ellis-van Creveld syndrome was created and *EVC* knockout mice were observed to develop shortened ribs, shortened limbs, and dental abnormalities (Ruiz-Perez et al., PMID: 17660199). This study also demonstrated that with the loss of *EVC* the downstream Ptch1 and Gli1 genes had reduced expression and caused Hedgehog signaling defects. Another mouse model created by Nakatomi et al. (PMID: 23315474) found that the absence of *EVC* caused varying defects in molar tooth development. Finally, a mouse model created by Caparros-Martin et al. (PMID: 23026747) investigated *EVC* knockout and *EVC2* knockout mice (single and double homozygous mutants). The skeletal phenotypes between these mouse models were indistinguishable. This study also noted that the *EVC* and *EVC2* complex are mutually required for expression in the cilium and promote Hedgehog signaling that is necessary for normal endochondral bone formation. More evidence is available in the literature, but the maximum score for experimental evidence (6 points) has been reached. In summary, there is definitive evidence supporting the relationship between *EVC* and autosomal recessive Ellis-van Creveld syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date September 24th, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0008673

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0008673

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: Natera

Inheritance Pattern: Unknown

Disease ID:MONDO:0008673

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: Myriad Women's Health