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Genetic epilepsy syndromes

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 4 panels

3 reviews

Helen Lord (Oxford Medical Genetics Laboratories)

Green List (high evidence)

On OMIM: 618362. AD CSS8. Machol et al, 2019 (30580808) - 15 unrelated individuals with impaired intellectual developemnt , 2 individuals prev reported by Zhou et al and Martinez et al. 4/15 had seizures. 13 het mutations identified - 12 de novo, 2 parental samples unavailable and 1 inherited from aff father - in whom it was de novo. The mutations clustered in the SWIRM and SANT domains of the protein.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

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

Rebecca Foulger (Genomics England curator)

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.
Created: 9 Sep 2019, 10:44 a.m. | Last Modified: 9 Sep 2019, 10:44 a.m.
Panel Version: 1.321
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262
Comment on list classification: Updated rating from Grey to Green following review from Konstantinos Varvagiannis highlighting recent paper: PMID:30580808 (Machol et al., 2019) report on 15 unrelated individuals with harbouring one of 13 heterozygous pathogenic SMARCC2 variants, with seizures reported in 4 of the individuals. Therefore sufficient unrelated cases of seizures in this paper for diagnostic-rating. 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, 4:51 p.m.
Comment on mode of inheritance: Monoallelic MOI supported by PMID:30580808.
Created: 25 Feb 2019, 4:18 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, 4:18 p.m.

Konstantinos Varvagiannis (Other)

I don't know

Gene present in the ID panel :

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.

As a result, this gene should be considered for inclusion in this panel as amber (or green).
Sources: Literature
Created: 20 Dec 2018, 11:51 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; Seizures

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review Green
Phenotypes
  • Coffin-Siris syndrome 8, 618362
  • 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
unknown
Publications
Panels with this gene

History Filter Activity

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to SMARCC2.

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to SMARCC2.

9 Sep 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: SMARCC2 were changed from Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features to Coffin-Siris syndrome 8, 618362; 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: 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: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: SMARCC2 were changed from Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck; Seizures 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: 0

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

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

25 Feb 2019, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: SMARCC2 were set to 27392482

20 Dec 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: SMARCC2 was added gene: SMARCC2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: SMARCC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SMARCC2 were set to 27392482 Phenotypes for gene: SMARCC2 were set to Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck; Seizures Penetrance for gene: SMARCC2 were set to unknown Review for gene: SMARCC2 was set to AMBER