MTOR was FIRST reported in relation to overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes in 2012 (Lee et al. PMID:22729223). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Multiple recurrent variants have been identified in this gene, and functional testing in patient cell lines support a gain-of-function disease mechanism. Additional experimental studies have been done on non-patient derived cells and animal models supporting a gain-of-function disease mechanism. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity, Focal cortical dysplasia, type II, somatic (OMIM: 607341), Smith-Kingsmore syndrome (616638). The phenotypic spectrum is largely due to what tissue(s) the variant affects. In summary, MTOR has been definitively associated with overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 05/25/2021. (SOP v8)
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.