The relationship between AMACR and alpha-methylacyl-CoA racemase (AMACR) deficiency (congenital bile acid synthesis defect type 4 included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of September, 2019 and updated as of March 2022. AMACR encodes an enzyme that interconverts pristanoyl-CoA and C27-bile acylCoAs between their (R)- and (S)-stereoisomers. The conversion to the (S)-stereoisomers is necessary for degradation of these substrates by peroxisomal beta-oxidation. Patients with AMACR variants present typically with neuropathy and retinitis pigmentosa, with elevated pristanic acid levels. AMACR was first reported in relation to autosomal recessive AMACR deficiency in 2000 (Ferdinandusse et al, PMID: 10655068).
Summary of Case Level Data (8.1 points): At least 8 patients across 7 publications have been reported with the same homozygous missense variant, Ser52Pro (PMIDs: 10655068, 12512044, 21686617, 21576695, 20821052, 15249642, 33047465). A few other missense variants have also been reported (PMID: 10655068, 20921516, 23286897, 34267495). A deletion encompassing 5 genes including AMACR is reported in a patient with oculocutaneous albinism and AMACR deficiency (PMID: 22987308). This evidence cannot be scored in the GCI, but warrants a score of 1 point. The mechanism is expected to be homozygous loss of function.
Summary of experimental data (2 points): This gene-disease association is supported by a mouse model that recapitulates the human biochemical phenotype (PMID 25168382). The enzyme is highly expressed in peroxisomes, followed by mitochondria (PMID: 7649182).
In summary, this gene-disease relationship of AMACR and AMACR deficiency is classified as Moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
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.