ARG1 was first reported in relation to autosomal recessive inheritance of hyperargininemia in 1990 (Haraguchi et al., 1990, PMID: 2365823). At least 43 unique variants (including many missense and nonsense, as well as some in-frame indel, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in the gene have been reported in at least 11 probands in 5 publications (PMIDS: 23859858, 1463019, 1598908, 2365823, 29443755). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function. This gene-disease relationship is supported by the biochemical function of ARG1, catalyzing the final step of the urea cycle (PMID: 16747805), and two knockout mouse models which share the biochemical manifestations of hyperammonemia and hyperargininemia while lacking the clinical phenotypes of humans (PMIDs: 12052859, 23920045). In summary, ARG1 is definitively associated with autosomal recessive inheritance of hyperargininemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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.