RPS6KA3 (aka RSK2) was first reported in relation to X-linked Coffin-Lowry syndrome in 1996 (Trivier et al., PMID 8955270). At least 141 variants (missense, in-frame indel, nonsense, frameshift, large deletion) have been reported in humans (PMIDs 16879200, 8955270, 9837815, 10094187, 9832033). Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. For the purposes of this curation 11 patients with variants in this gene were scored in 2 publications (PMIDs 10094187, 11180593). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is X-linked loss-of-function (PMIDs 11180593, 10094187). This gene-disease association is supported by at least two separately generated knockout mouse models, cell culture models, functional alteration studies, and expression studies during human development (PMIDs 14678837, 26398944, 11113183, 17033934, 20832397). In summary, RPS6KA3 is definitively associated with X-linked Coffin-Lowry 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 ID/Autism Expert Panel on 5/28/2019 (SOP Version 6).
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).
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