ALG12 was first reported in relation to autosomal recessive ALG12-congenital disorder of glycosylation (also known as congenital disorder of glycosylation type Ig) in 2002 (Chantret et. al., PMID 11983712). Common phenotypes include intellectual disability, hypotonia, dysmorphic features, coagulation abnormalities and genitourinary abnormalities. Twenty-two unique variants (missense, nonsense, frameshift and an in-frame indel) that have been reported in 14 individuals across 11 publications (PMIDs: 11983712, 12093361, 12217961, 15639192, 16435218, 17506107, 25019053, 31529350, 34092405, 34467644, 34602961) are included in this curation. Several variants were evaluated but not scored due to high allele frequency in gnomAD (PMID: 31743061), discordant phenotypes (PMIDs: 31481313, 32530140), or lack of supporting biochemical evidence (PMID: 33461977). The mechanism of pathogenicity is known to be loss-of-function.
This gene-disease association is also supported by biochemical evidence. The protein encoded by ALG12 is involved in the N-linked glycoprotein synthesis pathway; loss-of-function of different proteins in this pathway have been associated with intellectual disability (PMID: 23798010).
In summary, there is definitive evidence to support the relationship between ALG12 and autosomal recessive ALG12-congenital disorder of glycosylation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 15, 2023 (SOP Version 9).
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).
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