Intellectual disability - microarray and sequencing
Gene: BCORL1 Amber List (moderate evidence)Comment on list classification: Kept rating Amber in line with the previous review by Rebecca Foulger. Severe ID only exhibited by 2/4 families. No additional papers recently published.Created: 13 Oct 2020, 9:29 a.m. | Last Modified: 13 Oct 2020, 9:29 a.m.
Panel Version: 3.430
Green List (high evidence)
Four unrelated families reported with variable ID, now has OMIM#, and original variant no longer listed as VOUS.Created: 29 Jan 2020, 10:25 a.m. | Last Modified: 29 Jan 2020, 10:25 a.m.
Panel Version: 3.0
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
Shukla-Vernon syndrome, MIM# 301029
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Updated rating from Red to Amber based on external review by Konstantinos Varvagiannis and the new paper Shukla et al., 2019 (PMID:30941876). The original Asn820Ser variant from Schuurs-Hoeijmakers et al., 2013 (PMID:24123876) is still listed as a VUS in OMIM due to a lack of evidence for association with the ID phenotype. Although Shukla et al report 3 cases with 3 new BCORL1 variants (two unrelated males and a further three brothers), patient 2 does not have ID, but instead has typical early motor milestones, and speech delay. ID is also mild in Patient 1. Based on 2 clear cases plus 1 potential case from Shukla et al,. I have rated Amber and added a 'watchlist' tag awaiting further reports.Created: 6 Jun 2019, 10:27 a.m.
I don't know
This gene may be considered for upgrade probably to amber (or green).
Schuurs-Hoeijmakers et al. (2013 - PMID: 24123876) reported briefly on 2 males with hypotonia, severe ID and similar facial features. Both harbored a BCORL1 missense variant (NM_021946.4:c.2459A>G or p.Asn820Ser) inherited from their (probably) unaffected mother (X-linked gene). The authors comment that BCORL1 encodes a transcriptional corepressor interacting with class II histone acetyltransferases and deacetylases and appears to be expressed in brain/neuronal tissue.
Shukla et al. (2019 - PMID: 30941876) report on 5 males from 3 families with DD, ID (4/5 - in 1 individual mild, in 3 further sibs severe), ASD (5/5) or additional behavioral abnormalities and/or some other possibly overlapping features. All individuals were found to be hemizygous for BCORL1 missense variants (in all cases inherited). The following variants were reported : c.2345T>A or p.Val782Glu, c.1487C>T or p.Ser496Phe and c.95C>T or p.Pro32Leu (NM_021946.4). The mother of one subject (with mild ID) had some degree of learning disabilities, anxiety and ADHD. One individual without apparent ID had inherited the variant from his mother who had normal educational attainment.
There are no functional studies (or X-inactivation studies in females) performed in any of these articles.
BCORL1 is not associated with any phenotype in OMIM/G2P. The gene is included in gene panels for intellectual disability offered by several diagnostic laboratories (incl. Radboud UMC).Created: 14 Apr 2019, 6:07 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Global developmental delay; Intellectual disability; Autism; Behavioral abnormality
Publications
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
Not associated with phenotype in OMIM or G2P. One variant reported as a heterozygote in two brothers with severe intellectual disability, however also present in unaffected mother, therefore classes as a VUSCreated: 15 Dec 2017, 9:38 a.m.
Mode of inheritance
Unknown
Publications
Red List (low evidence)
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Red List (low evidence)
Phenotypes for gene: BCORL1 were changed from Intellectual disability, developmental delay and dysmorphism; Behavioral abnormality to Shukla-Vernon syndrome, 301029
Publications for gene: BCORL1 were set to 24123876; 24896178; 26350204; 30941876
Gene: bcorl1 has been classified as Amber List (Moderate Evidence).
Tag watchlist tag was added to gene: BCORL1.
Gene: bcorl1 has been classified as Amber List (Moderate Evidence).
Publications for gene: BCORL1 were set to 24123876; 24896178; 26350204
Phenotypes for gene: BCORL1 were changed from to Intellectual disability, developmental delay and dysmorphism; Behavioral abnormality
Mode of inheritance for gene: BCORL1 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
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.
Model of inheritance for gene BCORL1 was set to Unknown Publications for gene BCORL1 was set to ['24123876', ' 24896178', ' 26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
BCORL1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
BCORL1 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).
OR
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).
OR
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.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
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.