GRIA3 was first reported in relation to X-linked Intellectual Disability in 1999 (Gecz et al., 10644433). At least 10 probands with missense variants have been reported in 8 publications (31406558, 28708303, 25644381, 26637798, 21376300, 24721225, 29016847, 17989220). In addition, loss of function variants in GRIA3 coding region have been reported in 3 probands (1 nonsense, 1 frameshift and 1 intragenic duplication) in 3 publications (PMIDs 31406558, 25644381, 17568425). The proband with 498Kb duplication variant was unable to be formally scored in the GCI since it is >10Kb in size. Though the genetic evidence score shown in the evidence summary is 7.6 points, it should be 8.6 points to account for this duplication variant that could not be scored. Variants in this gene also segregated with disease in at least 2 families (PMID 17989220). This gene-disease association is supported by animal models and expression studies (10644433, 12848940, 18312590,16436610, 22285418). In summary, there is sufficient evidence to support a definitive association of GRIA3 with X-linked complex neurodevelopmental disorder. The gene-disease association has been demonstrated in multiple reports and animal model studies, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/06/19 (SOP Version 7).
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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