COG3

Inheritance Pattern: AR

Disease ID:MONDO:0015286

Submitter: ClinGen

*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)

Inheritance Pattern: AR

Disease ID:MONDO:0957820

Submitter: Ambry Genetics