The relationship between the SLC38A9 gene and lysosomal storage disorders was evaluated using the ClinGen Clinical Validity Framework as of July 21, 2022. SLC38A9 encodes solute carrier family 38, member 9, a lysosomal amino acid transporter protein involved in regulating the mechanistic target of rapamycin complex 1 (mTORC1), via modulating transport of amino acids that stimulate mTORC1 activation (PMID: 25561175, PMID: 25567906) and mediating cholesterol-driven mTORC1 activation (PMID: 28336668).
To our knowledge, SLC38A9 has not been reported in association with human disease to date. Based on published experimental data, there is minimal evidence suggesting a role for SLC38A9 in lysosomal storage disorders. This experimental evidence (4.50 points total) includes: the biochemical function of the gene product (solute carrier family 38, member 9) being consistent with altered amino acid-mediated signaling of mTORC1 (PMID: 25561175); the physical interaction between SLC38A9 and NPC intracellular cholesterol transporter 1 (PMID: 28336668), a protein encoded by the NPC1 gene, which has been curated as Definitively associated with the lysosomal storage disease Niemann-Pick disease type C1 by the ClinGen Lysosomal Diseases GCEP; functional alteration (impaired amino acid-mediated signaling of mTORC1 in HEK293T cells harboring SLC38A9 variants lacking key amino acid residues involved in interacting with the Ragulator complex (PMID: 25567906); rescue of HEK293T cells harboring SLC38A9 variants lacking key amino acid residues involved in interacting with the Ragulator complex by reexpression of the segment containing these residues (PMID: 25567906); and the abnormal amino acid metabolism seen in a SLC38A9 knockout zebrafish model (PMID: 35457018).
In summary, there is currently no direct evidence supporting the association between the SLC38A9 gene and lysosomal storage disorders. There is minimal experimental evidence suggesting that the SLC38A9 gene may play a role in lysosomal storage disorders via its role in regulating mTORC1, but additional publications, including those involving human cases, are needed to define the role of the SLC38A9 gene in lysosomal storage disorders. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on August 2, 2022 (SOP v9).
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.