Primary ciliary dyskinesia (PCD) is a rare genetic condition belonging to the class of motile ciliopathies and is caused by abnormal structure, function, and biogenesis of motile cilia, a complex organelle present on the majority of the human cell surfaces. Ciliary abnormalities lead to the wide spectrum of symptoms manifested in various organ systems, resulting in neonatal respiratory distress in the term neonates, chronic oto-sino-pulmonary disease, organ laterality defects, infertility in males, and subfertility in females. PCD can be diagnosed by clinical phenotype, ciliary ultrastructural analysis, and molecular analysis. However, diagnosis can be challenging due to an overlap of clinical phenotype with other diseases, such as cystic fibrosis and primary immunodeficiency, variability of ciliary ultrastructure, which tends to be normal in ~30% of the cases, and extensive genetic heterogeneity. Currently, over 45 genes have been associated with PCD and motile ciliopathies, which are being curated under the auspices of the ClinGen Motile Ciliopathy GCEP. But in order to aid with the molecular diagnosis, it becomes pertinent to classify the variants in the curated genes such that it helps with the genetic diagnosis, and hence this VCEP has been established.

The first objective of the VCEP is the adaptation and validation of the ACMG/AMP standards and guidelines for interpreting sequence variants (Richards et al., 2015) for DNAH5 variations, the most frequent etiology PCD. This will be carried out in three stages: (1) a systematic review of all rules and the development of proposed adjustments approved by the VCEP, (2) testing of the proposed rules using a representative set of at least 40 DNAH5 variants and (3) refining rule adjustments as needed based on scenarios encountered during the testing phase.

The second objective is to classify variants reported in databases (ClinVar, OMIM) and/or the literature for DNAH5. Variant classification will focus on variants with conflicting interpretation in ClinVar while prioritizing the most common genes and variants associated with PCD.

In the future, the VCEP will develop and validate variant classification rules to curate variants in other PCD genes whose loss-of-function, like DNAH5, also corresponds to an absence of or defects in outer dynein arms (DNAI1, DNAI2, ODAD1, ODAD2, ODAD3, ODAD4). The VCEP will focus only on genes with strong or definitive evidence that variation causes PCD, as determined by the Motile Ciliopathy GCEP.