EVC2

Inheritance Pattern: AD

Disease ID:MONDO:0008673

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0008673

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0008673

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: ClinGen

*EVC2* was first reported in relation to autosomal recessive Ellis-van Creveld Syndrome (EvC) in 2002 (Galdzicka et al. 2002, PMID: 12468274). Ellis-van Creveld Syndrome is associated with reduced stature, shortened limbs, post-axial polydactyly of hands and/or feet, dysplastic nails and teeth, and cardiac defects. Weyer’s acrofacial dysostosis is characterized by postaxial polydactyly of hands and/or feet, dysplastic nails, dental abnormalities, but no cardiac involvement. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, Ellis-van Creveld Syndrome (OMIM:225500) and Weyer’s acrofacial dysostosis (OMIM: 193530). The split curation for autosomal dominant Weyer’s acrofacial dysostosis has been curated separately. Nine variants (missense, indel, nonsense, frameshift), that have been reported in sixteen probands in five publications (PMIDs: 12468274, 12571802, 19810119, 23220543, 38531627) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function due to nonsense mediated decay. This gene-disease relationship is also supported knockout animal models, expression studies, biochemical function, and protein interaction (PMIDs: 19810119, 23026747, 26219237, 27164562, 38531627). *EVC2* is a transducer of extracellular signals and positively regulates Hedgehog (Hh) which is associated with bone formation and limb development and is required for cilliogenesis (PMID: 19810119). Disruption of *EVC2* in animal models with conventional and conditional knockouts resulted in skeletal defects of limbs and crania, as well as reduced growth and reduction or no expression of *EVC2* in cilia (PMIDs: 23026747, 26219237, 27164562). In summary, there is definitive evidence supporting the relationship between *EVC2* 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 Skeletal Disorders GCEP on the meeting date February 2, 2026 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: PanelApp Australia

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: Myriad Women's Health

Inheritance Pattern: AD

Disease ID:MONDO:0008673

Submitter: ClinGen

*EVC2* was first reported in relation to autosomal dominant Weyer’s acrofacial dysostosis (WAD) in 2006 (Ye et al. 2006, PMID: 16404586). Weyer’s acrofacial dysostosis is characterized by postaxial polydactyly of hands and/or feet, dysplastic nails, dental abnormalities, but no cardiac involvement. Ellis-van Creveld Syndrome is associated with reduced stature, shortened limbs, post-axial polydactyly of hands and/or feet, dysplastic nails and teeth, and cardiac defects. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, Ellis-van Creveld Syndrome (OMIM:225500) and Weyer’s acrofacial dysostosis (OMIM: 193530). The split curation for autosomal recessive Ellis-van Creveld Syndrome has been curated separately. Five variants (nonsense, frameshift), that have been reported in 27 probands in five publications (PMIDs: 16404586, 18182642, 19810119, 23220543, 38531627) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be dominant negative, as premature termination codons generated in exon 22 of *EVC2* do not undergo nonsense mediated decay potentially resulting in interference of normal protein function. This gene-disease relationship has minimal direct experimental evidence, as all animal models of *EVC2* are full gene knockouts or targeted to non-exon 22 regions. *EVC2* is a transducer of extracellular signals and positively regulates Hedgehog (Hh) which is associated with bone formation and limb development and is required for ciliogenesis, and loss of the last 43 residues in *EVC2*, encoded by exon 22, can modify and disturb the Hedgehog signaling (PMID: 19810119). The extended pedigree of Ye et al. 2006 (PMID: 16404586) provides an estimated LOD of 3 and candidate gene sequence contributing one point of support. In summary, there is definitive evidence supporting the relationship between *EVC2* and autosomal dominant Weyer’s acrofacial dysostosis. 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 Skeletal Disorders GCEP on the meeting date February 2, 2026 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0009162

Submitter: Labcorp Genetics (formerly Invitae)