MAPKBP1 was first reported in relation to autosomal recessive nephronophthisis in 2017 (Maria et al., PMID: 28089251). Ten variants (nonsense, frameshift, missense) that have been reported in 11 probands in 4 publications (PMIDs: 28089251, 32505465, 33623699, 35140360) are included in this curation. All but two of the variants are null, indicating that this disease is largely caused by a loss-of-function mechanism. The maximum score for genetic evidence (12 pts.) was reached. This gene-disease relationship is also supported by experimental evidence (expression-level evidence, functional alteration evidence; PMID: 28089251). Expression analysis showed that the encoded protein is expressed in tubular epithelial cells and glomeruli of the adult kidney. Analysis of inner medullary collecting duct cells shows increased DNA Damage Response signaling in mutants, consistent with the human phenotype. This gene-disease pair was originally evaluated by the ClinGen Kidney Cystic & Ciliopathy GCEP on 5/26/2021, and re-evaluated on 6/10/2024. Even though there was only one new case (PMID: 35140360) and no new experimental evidence, the panel felt that there was ample genetic evidence, with supporting functional evidence for many of the mutations, that outweighed the limited other experimental evidence. As a result of this reevaluation, the classification increased from Strong to Definitive supporting the relationship between MAPKBP1 and autosomal recessive nephronophthisis that has been demonstrated in both the research and clinical diagnostic settings, and upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 6/10/2024 (SOP Version 10).
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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