COG3 was first reported in relation to an autosomal recessive congenital disorder of glycosylation in 2023 (Duan et al., PMID: 37711075). Two families have been reported with biallelic variants in the gene. These individuals presented with global developmental delay and severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings. Serum transferrin studies, carried out for affected individuals in one of the families showed reduced sialylation.
Congenital Disorder of Glycosylation (specifically Congenital disorder of glycosylation, type IIbb, MIM# 606975; also known as COG3-CDG) is the only monogenic disorder asserted to be caused by variants in COG3.
Two different missense variants have been reported, each in one of the two reported families (Duan et al, 2023, PMID: 37711075). The mechanism of disease is unknown but assumed to be loss of function. (Total points for genetic evidence = 1.5 points)
This gene-disease relationship is also supported by experimental evidence including the biochemical function of COG3, a subunit of the COG complex, which is important in intra Golgi and Golgi to ER retrograde transport (Zolov and Lupashin, 2005, PMID: 15728195; Shestakova et al, 2006, PMID: 16420527), protein interaction studies showing physical interaction of COG3 with other COG subunits that have been implicated in CDG (Lees et al, 2010, PMID: 20972446; Ishii et al, 2018, PMID: 29899178), and functional alteration studies in patient and non-patient cells showing defects in retrograde transport (Duan et al, 2023, PMID: 37711075; Pokrovskaya et al, 2011, PMID: 21421995). (Total points for experimental evidence = 5 points).
In summary, there is limited evidence supporting the relationship between COG3 and an autosomal recessive congenital disorder of glycosylation. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on September 18, 2024 (SOP Version #11)
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.