Intellectual disabilityGene: SMARCC2 Green List (high evidence)
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
Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
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.
Red List (low evidence)
Gene: smarcc2 has been classified as Green List (High Evidence).
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
Publications for gene: SMARCC2 were set to 26350204; 27392482
Publications for gene: SMARCC2 were set to 26350204
Mode of inheritance for gene: SMARCC2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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.
Publications for gene SMARCC2 was set to ['26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
SMARCC2 was added to Intellectual disabilitypanel. Sources: Expert Review Red
SMARCC2 was created by ellenmcdonagh
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.