Submission Details

EMC1 is a component of the EMC complex, a multifunctional, multi-subunit protein complex involved in insertion of trans-membrane domains with low hydrophobicity into the ER membrane. EMC1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder with motor features in 2016 (Harel et al., PMID 26942288). EMC1 has been noted to be associated with the following disease entities: Cerebellar atrophy, visual impairment, and psychomotor retardation (MIM:616875) and Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome (ORPHA:480898). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern. The split curation for autosomal recessive complex neurodevelopmental disorder with motor features has been curated separately. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 4 POINTS. 4 unique variants (all missense variants) that have been reported in 4 probands in 2 publications (PMIDs: 26942288, 35234901) are included in this curation. Structural modelling suggests that these variants cluster within the beta-propeller domain of the EMC1 protein (PMID: 35234901). For 3/4 of these variants, additional functional evidence is provided by failure of the mutant proteins to rescue phenotypes in a Drosophila model. This gene-disease association is also further supported by this Drosophila model, where knockdown in glia resulted in reduced viability and a motor phenotype which were rescued by expression of human wildtype EMC1 (PMID: 35234901). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy GCEP on the meeting date 6th October 2022 (SOP Version 9).