TRPM3 was first reported in relation to autosomal dominant intellectual disability and epilepsy in 2019 (Dyment et al., PMID: 31278393). Phenotypic features include congenital hypotonia, global developmental delays, variable intellectual disability, ophthalmologic findings including strabismus and nystagmus, musculoskeletal findings including hip dysplasia, scoliosis, and club foot, variable seizure and epilepsy classifications, MRI abnormalities, and distinctive dysmorphic features. This curation includes 12 heterozygous missense variants reported in 12 probands with phenotypic similarity (PMIDs: 31278393, 34074259, 36648066, 37684057). Of these 12 heterozygous missense variants, 9 have functional data to support a gain of function effect. All distinct variants available in the literature are scored. Additional probands are reported in the literature, but all harbor variants already included in the curation. As the maximum score for genetic evidence (12 points) has already been reached, those individuals were not included in this curation.
In summary, there is definitive evidence supporting the relationship between TRPM3 and autosomal dominant syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in the clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on the meeting date May 23, 2024 (SOP Version 10).
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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