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Intellectual disability

Gene: SMARCC2

Green List (high evidence)

SMARCC2 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 2)
EnsemblGeneIds (GRCh38): ENSG00000139613
EnsemblGeneIds (GRCh37): ENSG00000139613
OMIM: 601734, Gene2Phenotype
SMARCC2 is in 5 panels

4 reviews

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Machol et al. (https://doi.org/10.1016/j.ajhg.2018.11.007) report on 15 unrelated individuals with heterozygous pathogenic SMARCC2 variants.

SMARCC2 (BAF170) is one of the subunits of the chromatin remodeling BAF complex and the phenotype of these subjects resembled the phenotype of other "BAFopathies", notably Coffin-Siris and Nicolaides-Baraitser syndrome. DD and/or ID were universal features (a few individuals were too young). Other common features included speech impairment, hypotonia, feeding problems, behavioral anomalies as well as some overlapping facial features (similar to other BAFopathies). Seizures were noted in 4/15 individuals.

8 missense variants, 1 in-frame deletion, 4 splice-site variants, 1 frameshift and 1 nonsense variant are reported. De novo occurrence was the case for 12 of these variants while for 2 individuals one/both parents were unavailable. One subject with mild DD had inherited a nonsense variant from his affected father (with borderline ID) in whom the mutation had occurred as a de novo event.

Several of the missense variants (but not all) clustered in the SANT domain, while individuals with the specific variants seemed to present with a more severe phenotype.

The de novo in-frame deletion, which was observed in one mildly affected individual, has been reported once in gnomAD.

Exon skipping was demonstrated for 1 splice-site variant while expression studies for another splice-site variant showed reduced mRNA expression. mRNA expression was normal for the in-frame deletion.

Similarly to what has been observed in other disorders of this group, some mutations are thought to act through a dominant-negative mechanism.

Transcriptome analysis in fibroblasts from affected individuals suggested the presence of a group of differentially expressed genes possibly involved in regulation of neuronal development/function.

As the authors note, studies in Smarcc2-deficient mice suggest a role in learning as well as behavioral adaptation (PMID: 27392482).

SMARCC2 is not associated with any phenotype in OMIM, nor in G2P.

The gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc - participating in this study).

As a result, this gene should be considered for upgrade to green.
Created: 20 Dec 2018, 11:46 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck

Publications

Variants in this GENE are reported as part of current diagnostic practice

Caroline Wright (Sanger)

Red List (low evidence)

Rebecca Foulger (Genomics England curator)

Red List (low evidence)

Comment on list classification: Updated rating from Red to Green following review from Konstantinos Varvagiannis and recent paper: PMID:30580808 (Machol et al., 2019) report on 15 unrelated individuals with varying degrees of neurodevelopmental delay in all 15 cases, harbouring one of 13 heterozygous pathogenic SMARCC2 variants. Therefore sufficient unrelated cases in this paper to support causation. Konstantinos Varvagiannis notes that SMARCC2 is not yet associated with a phenotype in OMIM or Gene2Phenotype, but this is most likely because the 2019 paper PMID:30580808 has not yet been curated in these databases.
Created: 25 Feb 2019, 4:13 p.m.
Comment on publications: PMID:27392482 (Tuoc et al., 2017, demonstrating a mouse model of learning and memory as included in the review by Konstantinos Varvagiannis) use BAF170 nomenclature; BAF170 is a synonym of SMARCC2.
Created: 25 Feb 2019, 4 p.m.
Comment on mode of inheritance: Monoallelic MOI supported by PMID:30580808.
Created: 25 Feb 2019, 3:59 p.m.
Candidate ID gene in PMID:26350204 but no strong evidence to support ID causation.
Created: 31 Oct 2017, 9:24 a.m.

Publications

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • neurodevelopmental delay and growth retardation
  • prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features
OMIM
601734
Clinvar variants
Variants in SMARCC2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

25 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: smarcc2 has been classified as Green List (High Evidence).

25 Feb 2019, Gel status: 1

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: SMARCC2 were changed from to Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features

25 Feb 2019, Gel status: 1

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: SMARCC2 were set to 26350204; 27392482

25 Feb 2019, Gel status: 1

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: SMARCC2 were set to 26350204

25 Feb 2019, Gel status: 1

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: SMARCC2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

29 Nov 2017, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene SMARCC2 was set to ['26350204']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

SMARCC2 was added to Intellectual disabilitypanel. Sources: Expert Review Red

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

SMARCC2 was created by ellenmcdonagh