RIN2 was first reported in relation to RIN2 syndrome (formerly MACS syndrome), an autosomal recessive lysosomal disease, in 2009 (Basel-Vanagaite L, et al.; PMID: 19631308). RIN2 encodes RAS and RAB interactor 2 and biallelic mutations in this gene are reported to cause cell trafficking dysfunction. Individuals with RIN2 syndrome have varying clinical features including macrocephaly, coarsening of facial features, down-slanting palpebral fissures, full everted lips, soft redundant skin, gum hypertrophy, irregular dentition, sparse scalp hair, joint hypermobility, and scoliosis. Four frameshift variants that have been reported in four probands in four publications (PMIDs: 19631308, 20424861, 24449201, 30769224) are included in this curation. In all cases, the variants presented in homozygosity. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by expression studies that show this gene is expressed in fibroblasts, a relevant tissue, and studies showing that the expression level of the gene was markedly decreased when analyzed by qRT-PCR and absent when analyzed by immunoblotting (PMID: 19631308). In summary, there is definitive evidence supporting the relationship between RIN2 and autosomal recessive RIN2 syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP on December 4, 2023 (SOP Version 9).
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.