STIM1 was first reported in relation to autosomal recessive combined immunodeficiency in 2009 (Picard et al., PMID: 19420366). Variants in STIM1 have been reported in individuals with the following disease entities: autosomal dominant tubular aggregate myopathy and autosomal recessive combined immunodeficiency. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability between these disease entities. Therefore, the following disease entities have been split: tubular aggregate myopathy MONDO:0008051, combined immunodeficiency due to STIM1 deficiency MONDO:0013008. The split curation for autosomal dominant tubular aggregate myopathy has been curated separately.
Combined immunodeficiency due to STIM1 deficiency is characterized by defective regulatory T cell activity. Clinical presentation is variable but often includes early-onset recurrent infections, autoimmunity, non-progressive myopathy, ectodermal dysplasia, iris hypoplasia, and developmental delay. Heterozygotes are not known to be clinically affected.
Five variants including nonsense, frameshift, splice site, and gross deletion have been reported in five probands in five publications and are included in this curation (PMIDs: 19420366, 20876309, 33733462, 37898571, 38578569). Segregation with disease has been observed within families. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function.
This gene-disease relationship is also supported by functional and rescue assays (PMIDs: 19420366, 20876309). Patient cells show defective store-operated Ca2+ entry (SOCE), and expression of wild-type STIM1 restores SOCE.
In summary, there is definitive evidence supporting the relationship between STIM1 and autosomal recessive combined immunodeficiency. 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 SCID/CID GCEP on the meeting date August 21, 2025 (SOP Version 11).
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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