Submission Details

COG1 was first reported in relation to autosomal recessive Congenital Disorders of Glycosylation by Foulquier F, et al., in 2006 (PMID: 16537452). At least 5 unique variants, some missense and intronic variants, have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental findings. Variants in this gene have been reported in at least 5 probands from publications (PMIDs: 16537452, 19008299, 25533962, 33960418, 34625039). Mutations in COG1 can lead to Congenital disorder of glycosylation (CDG), type Iig. CDGs result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor delay, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. Clinical features of CDG-II caused by Cog1 deficiency include failure to thrive, generalized hypotonia, growth delay and mild psychomotor delay. No supporting segregation information is available, and the disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is supported by the biochemical function of COG1, the protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. Knockout of COG1 exhibited distribution of the interaction of the subunits in the complex (PMID: 15932880). A different knockout experiment done in HEK293T displayed morphological changes in the Golgi structure, similar if not more serve changes that were previously observed in CHO cells (PMID: 27066481). Coimmunoprecipitation experiments showed interaction with other proteins in the COG complex, specifically its interaction with COG2, COG3, and *COG5 *(PMID: 11980916). In addition, the rescue of patient cells showed that overexpression of COG1 can restore the localization of the β-1,4 galactosyltransferase (PMID: 16537452). In summary, there is strong evidence supporting this gene-disease relationship. Although additional genetic and experimental evidence is needed to establish a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. A classification of MODERATE was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 1/4/23 (SOP Version 10)