Variants in ALG6 were first reported in individuals with autosomal recessive congenital disorder of glycosylation type 1C (also known as ALG6-CDG) in 1999 (HGNC:23157). Associated phenotypes include strabismus, seizures, truncal muscular hypotonia, intellectual disability, global developmental delay and ataxia (OMIM#603147). At least 41 affected individuals with variants in ALG6 have been reported in the literature, and variants have been observed to segregate with disease in several families (PMID: 27287710, PMID: 10359825, PMID: 20398363). A recurrent variant, A333V, has been observed across multiple ancestral groups. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
This gene-disease relationship is also supported by functional evidence demonstrating the impact of variants on the expression and structure of the encoded ALG protein (PMID: 10359825, PMID: 10914684, PMID: 11106564, PMID: 16007612).
In summary, there is definitive evidence supporting the relationship between ALG6 and ALG-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification has been approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 11, 2022 (SOP 9).
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