Submission Details

SMARCC2 is one of the core subunits of the SWI/SNF (BAF) chromatin remodeling complex. SMARCC2 was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2019 (Machol et al., PMID: 30580808). Variants in this gene had been previously reported in large cohort studies of individuals with intellectual disability, autism spectrum disorder or developmental disorders without detailed phenotype information (PMIDs: 25363760, 25590979, 27620904, 28135719, 28191889, 28263302). Features seen in affected individuals include global developmental delay and/or intellectual disability (85%), speech and motor deficits, behavioral abnormalities (60%), including autism or autistic behavior (34%), hypotonia (69%), brain imaging abnormalities (61%), feeding difficulties/failure to thrive (51%), facial dysmorphism (45%), visual impairment (33%), seizures (28%), scoliosis (28%), and short stature (24%). Although some individuals exhibit clinical features that overlap with Coffin-Siris syndrome, the overall phenotypic manifestations appear to be non-recognizable (PMID: 37551667).

Twelve SMARCC2 variants (missense, nonsense, frameshift, splice, and inframe deletion) that have been reported in 19 probands in five publications (PMIDs: 25590979, 27620904, 30580808, 34881817, 37551667) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. All non-truncating variants (missense, inframe deletions, and splice variants shown or predicted to result in inframe deletions) occur de novo, whereas most truncating variants are inherited from unaffected parents, though they can also occur de novo (PMID: 37551667). The mechanism of pathogenicity of the truncating variants is assumed to be haploinsufficiency, while the mechanism of the non-truncating variants remains unknown. However, the clustering of missense and inframe variants in the SANT and CAR domains of the protein— which are involved in chromatin binding and the formation of the core BAF complex, respectively — suggests that these variants could exert a dominant-negative or gain-of-function effect (PMID: 37551667). While variants in other regions do not affect protein stability, the recurrent N-terminal missense variant p.Pro77Leu causes SMARCC2 protein loss (PMID: 37551667).

Individuals with non-truncating variants have a more severe phenotype, particularly with regard to neurodevelopment, growth parameters, and facial dysmorphisms (PMID: 37551667), in agreement with the de novo occurrence of these variants. In contrast, truncating variants have a milder impact, explaining their incomplete penetrance and frequent inheritance from a healthy parent. This genotype-phenotype correlation is supported by the observation that the missense variant p.Pro77Leu, which causes almost complete protein loss, was associated with a milder phenotype (PMID: 37551667).

This gene-disease relationship is also supported by experimental evidence, including biochemical function, protein interactions, and mouse models (PMIDs: 23643363, 27392482). Other subunits of the SWI/SNF complex have also been implicated in Coffin-Siris syndrome, including SMARCB1, SMARCA4, SMARCE1, SMARCD1, ARID1A, ARID1B, ARID2, DPF2, and BICRA.

In summary, there is definitive evidence supporting the relationship between SMARCC2 and autosomal dominant Coffin-Siris syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 2, 2022. It was reevaluated on September 17, 2025 (SOP Version 11). Although new evidence was added, the classification did not change.