ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 22q11.23|22q11
  • GRCh37/hg19 chr22: 24,129,118-24,176,705
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr22: 23,786,966-23,838,009
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000022.10) (NC_000022.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21108436 Eaton KW et al (2011) explored one hundred matched tumor and blood samples with rhabdoid tumors and identified that "thirty-five of one hundred patients were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions including regions both proximal and distal to SMARCB1." ? Putative LOF variants with unknown inheritance: total 9 cases ? Putative LOF variants, de novo: total 4 cases ? Segregation of putative LOF variants was described in 4 families. Gonadal mosaicism identified in 2 families. Of note, 4 carrier parents of affected individuals were themselves unaffected; this could be explained by the two-hit hypothesis.
29706634 Holsten T et al (2018) performed a meta-analysis to evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAF germline alterations. Their meta-analysis for SMARCB1 gene variants indicates: ? "whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma. ? "SMARCB1 germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies" ? "Truncating SMARCB1 variants (whole gene deletions, partial deletions, nonsense, and frameshift variants) are much more likely to be associated with malignancies, While partial and whole gene deletions of SMARCB1 only appear in the setting of rhabdoid tumors"
18285426 Hadfield et al (2008) identified novel, germline SMARCB1 mutations in five of 15 (33.3%) families and in two individuals from the 28 (7.1%) sporadic cases with clinical diagnoses of schwannomatosis. Identified mutations included one nonsense mutation (c.46A>T, p.K16X) in a single individual from an affected family (no other family members were available for testing). This mutation (in exon 1) was not present in databases of genomic variation or in a panel of 100 healthy control individuals.

Haploinsufficiency phenotype comments:

Germline variants in SMARCB1 has been implicated in benign and malignant tumors (rhabdoid tumor predisposition syndrome) as well as neurodevelopmental disorders ( Coffin-Siris syndrome). Different types of variants have been associated with different clinical phenotype (PMID:29706634). Whole gene as well as exon deletions and truncating variants are associated with malignancy and early-onset rhabdoid tumor predisposition syndrome. Constitutional (mostly de novo) variants of SMARCB1 as a first step followed by somatic loss-of-heterozygosity (LOH) or additional somatic loss-of-function variants represent a paradigmatic two-hit tumor model of epigenetic regulators(PMID: 17357086; 20848638; 1255467; 24123847; 21208904; 21108436). In contrast, non-truncating variants (especially missense or in-frame deletion variants in SMARCB1 CTD domain) are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma through a loss-of-function, gain-of-function or dominant negative effect (PMID:22426308; 29907796; 3175698). Of note, Tsurusaki et al. (2012) (PMID:22426308) identified 2 mutations in the SMARCB1 gene in 4 patients with a syndromic form of mental retardation that they authors classified as Coffin-Siris syndrome. Three patients carried the same in-frame deletion and 1 patient carried a missense mutation. These mutations were nontruncating, and the authors suggested a gain-of-function or dominant-negative mechanism for this phenotype.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Focal duplication of SMARCB1 is not identified. No evidence to evaluate for TS : 0