PRKCSH was FIRST reported in relation to autosomal dominant polycystic liver disease in 2003 (Li et al., PMID 12529853). Autosomal dominant polycystic liver disease due to PRKCSH mutations (ADPLD-PRKCSH) is diagnosed in adults with a family history of liver cysts, under age 40 with any number of liver cysts and individuals over the age of 40 with four or more liver cysts. Kidney cysts are present in approximately 28-35% of cases with absent to mild kidney disease and no association with progression to end stage renal disease (PMID 12529853, PMID 15057895, PMID 29038287). At least nine unique variants (e.g. nonsense, frameshift, splice site, missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data , population data and experimental data. Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least nine probands and in at least 5 publications (PMID 12529853, PMID 12577059, PMID 15057895, PMID 20095989, PMID 28375157). Variants in this gene segregated with disease in at least 109 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is heterozygous loss of function (PMID 12529853) with a secondary somatic hit resulting in loss of heterozygosity suggested (PMID 21856269). This gene-disease association is supported by expression studies in cell models, patient derived samples, and mouse models. In summary, PRKCSH is definitively associated with AUTOSOMAL DOMINANT POLYCYSTIC LIVER DISEASE. 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 Cystic and Ciliopathy Disorders GCEP on July 8th 2020 (SOP Version 7).
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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