STIM1 was first reported in relation to autosomal dominant tubular aggregate myopathy in 2013 (Bohm et al., PMID: 23332920). Variants in this gene have also been reported in association with Stormorken Syndrome, York Platelet Syndrome, and an Immunodeficiency phenotype (PMIDs: 25577287, 24591628, 24619930). Stormorken and York Platelet have been evaluated by ClinGen Lumping and Splitting guidelines and determined to be the same entity as Tubular Aggregate Myopathy with a spectrum of phenotypic severity. At least 17 unique predominantly missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 24 probands in 10 publications (PMIDs: 23332920, 25326555, 25577287, 24591628, 24619930, 28624464, 27876257, 24570283, 25953320, 27066587). Variants in this gene segregated with disease in a number of additional family members, however no families were large enough to draw meaningful evidence. More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is heterozygous gain of function, with alteration of particularly the EF-hand domain responsible for altered calcium signalling detection and resulting consitutive activation of store-operated calcium entry regardless of the intracellular calcium levels. (Morin et al. 2019, PMID: 31448844) This gene-disease association and mechanism is supported by several mouse and zebrafish models, biochemical function evidence, and functional studies. Each model recapitulates some amount of the phenotypes shown in humans including thrombocytopenia, muscle weakness, and muscle fiber atrophy. Additionally, STIM1's role in SOCE and the resulting always activated state when the expression and function of the protein is altered show clear correlations with the displayed phenotypes as both platelet function/clotting and skeletal muscle signalling relies on calcium flow. In summary, STIM1 is definitively associated with autosomal dominant tubular aggregate myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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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