ALG5 is located at chromosome 13q13.3 and encodes dolichyl phosphate glucosyltransferase, an transmembrane-bound enzyme of the endoplasmic reticulum that is involved in protein N-linked glycosylation via catalyzing the transfer of glucose from UDP glucose to dolichyl phosphate (PMID: 8076653). ALG5 was first reported in relation to autosomal dominant polycystic kidney disease(ADPKD) in 2022 (Lemoine H et al., 2022 PMID: 35896117). Common phenotypes for individuals ALG5 variants and ADPKD include late-onset development of CKD, atrophic kidneys, and multiple millimeter-sized kidney cysts (PMID: 35896117). Five unique variants (1 frameshift, 1 deletion, 1 nonsense, 2 missense) reported in five probands in one publication (PMID: 35896117) were included in this curation. The mechanism of pathogenicity is known to be loss-of-function. A total of 7.1 genetic evidence points was reached, considering case-level and segregation data. This gene-disease relationship is also supported by biochemical functional assay demonstrating that disruption of ALG5-mediated N-linked protein glycosylation leads to impaired maturation of polycystin 1 (PC1); impaired maturation of PC1 is implicated in the pathogenesis of cyst formation and polycystic kidney disease (PMID: 30523303). A total number of 0.5 experimental evidence points was reached. In summary, there is moderate evidence supporting the relationship between ALG5 and ADPKD. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 03/22/2023 (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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