ALPK3 encodes for protein α-kinase 3, an essential cardiac pseudokinase which functions to aid in myosin-mediated force buffering and sarcomere proteostasis. ALPK3 was first reported in relation to autosomal dominant HCM in 2018 (Jaouadi et al., 2018 PMID: 30046096). At least 38 variants (nonsense, frameshift, and splice site) have been reported in probands in five publications (PMIDs: 34263907, 32480058, 30046096, 33191771, 37973666) are included in this curation. Variants in this gene segregate in at least three families. Two case-control studies showed that the proportion of ALPK3 loss-of-function variants in cardiomyopathy cohorts was significantly higher than control cohorts. More evidence is available in the literature, however, the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is loss of function and this gene-disease relationship is supported experimental evidence included biochemical function, expression, and models (PMIDs: 11418590, 36321451, 39196058), reaching the maximum score of 6 with the inclusion of the a recent knock-in mouse model which demonstrated a hypertrophic response following chronic adrenergic challenge, and partial rescue of the cellular phenotype by Mavacamten (Leinhos L, et al., 2024 https://www.biorxiv.org/content/10.1101/2024.09.30.615779v1). In summary, ALPK3 has a strong association with autosomal dominant HCM; this has been demonstrated in both research and clinical settings. An analysis will be performed separately to determine the strength of evidence for ALPK3 in an autosomal recessive cardiomyopathy. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on December 19, 2023.
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.