Description
NOTE:
These data are for research purposes only. While the ClinGen data are
open to the public, users seeking information about a personal medical or
genetic condition are urged to consult with a qualified physician for
diagnosis and for answers to personal medical questions.
UCSC presents these data for use by qualified professionals, and even
such professionals should use caution in interpreting the significance of
information found here. No single data point should be taken at face
value and such data should always be used in conjunction with as much
corroborating data as possible. No treatment protocols should be
developed or patient advice given on the basis of these data without
careful consideration of all possible sources of information.
No attempt to identify individual patients should
be undertaken. No one is authorized to attempt to identify patients
by any means.
The Clinical Genome Resource (ClinGen)
tracks display data generated from several key curation activities related to gene-disease validity,
dosage sensitivity, and variant pathogenicity.
ClinGen is a National Institute of Health (NIH)-funded initiative dedicated to
identifying clinically relevant genes and variants for use in precision medicine and research.
This is accomplished by harnessing the data from both research efforts and clinical genetic
testing and using it to propel expert and machine-driven curation activities.
ClinGen works closely with the National Center for Biotechnology Information (NCBI) of the
National Library of Medicine (NLM)
which distributes part of this information through its ClinVar database.
The available data tracks are:
- ClinGen Dosage Sensitivity Map -Haploinsufficiency (ClinGen
Haploinsufficiency) and -Triplosensitivity (ClinGen Triplosensitivity) -
Shows evidence supporting or refuting haploinsufficiency (loss) and triplosensitivity (gain) as
mechanisms for disease at gene-level and larger genomic regions.
- ClinGen Gene-Disease Validity Classification (ClinGen Validity) -
Provides a semi-qualitative measurement for the strength of evidence of a gene-disease relationship.
- Clingen CSPEC variant interpretation VCEP specifications -
Identifies loci that have ClinGen criteria Specification (CSpec)
information. This is used and
applied by ClinGen Variant Curation Expert Panels (VCEPs) and biocurators in the classification of variants.
A rating system is used to classify the evidence supporting or refuting dosage
sensitivity for individual genes and regions, which takes in consideration the following criteria:
number of causative variants reported, patterns of inheritance, consistency of phenotype, evidence
from large-scale case-control studies, mutational mechanisms, data from public genome variation
databases, and expert consensus opinion.
The system is intended to be of a "dynamic nature", with regions being reevaluated periodically to
incorporate emerging evidence. The evidence collected is displayed within a publicly available
database.
Evidence that haploinsufficiency or triplosensitivity of a gene is associated with a specific
phenotype will aid in the interpretive assessment of CNVs including that gene or genomic region.
Similarly, a qualitative classification system is used to correlate the evidence of
a gene-disease relationship: "Definitive", "Strong", "Moderate",
"Limited", "Animal Model Only",
"No Known Disease Relationship", "Disputed", or "Refuted".
Display Conventions
Haploinsufficiency/Triplosensitivity tracks
Items are shaded according to dosage sensitivity type, red
for haploinsufficiency score 3, blue for triplosensitivity score 3,
and grey for other evidence scores or
not yet evaluated).
Mouseover on items shows the supporting evidence of dosage sensitivity.
Tracks can be filtered according to the supporting evidence of dosage sensitivity.
Dosage Scores are used to classify the evidence of the supporting dosage sensitivity map:
- 0 - no evidence available
- 1 - little evidence for dosage pathogenicity
- 2 - some evidence for dosage pathogenicity
- 3 - sufficient evidence for dosage pathogenicity
- 30 - gene associated with autosomal recessive phenotype
- 40 - dosage sensitivity unlikely
For more information on the use of the scores see the ClinGen
FAQs.
Gene-Disease Validity track
The gene-disease validity classifications are labeled with the disease entity and hovering
over the features shows the associated gene. Items are color coded based on the strength of their
classification as provided below:
| Color |
Classifications |
|
Definitive: The role of this gene in this particular disease has been
repeatedly demonstrated and has been upheld over time |
|
Strong: The role of this gene in disease has been independently
demonstrated typically in at least two separate studies, including both strong variant-level
evidence in unrelated probands and compelling gene-level evidence from experimental data |
|
Moderate: There is moderate evidence to support a causal role for this
gene in this disease, typically including both several probands with variants and moderate
experimental data supporting the gene-disease assertion |
|
Limited: There is limited evidence to support a causal role for this
gene in this disease, such as few probands with variants and limited experimental data supporting
the gene-disease assertion |
|
Animal Model Only: There are no published human probands with variants
but there is animal model data supporting the gene-disease assertion |
|
No Known Disease Relationship: Evidence for a causal role in disease
has not been reported |
|
Disputed: Conflicting evidence disputing a role for this gene in this
disease has arisen since the initial report identifying an association between the gene and disease |
|
Refuted: Evidence refuting the role of the gene in the specified
disease has been reported and significantly outweighs any evidence supporting the role |
The version of the ClinGen Standard Operating Procedures (SOPs) that each gene-disease
classification was performed with is provided as well. An older or newer SOP version does not
necessarily mean the classification is any more or less valid but is provided for clarity.
Each details page also contains a direct link to an evidence summary detailing the rationale behind
the specific classification and information such as a breakdown of the semi-qualitative framework,
relevant PubMed IDs, the type of data (Genetic vs Experimental Evidence), and a detailed summary.
These tracks are multi-view composite tracks that contain multiple data types (views). Each view
within a track has separate display controls, as described
here.
ClinGen VCEP Specifications track
Item names correspond to the VCEP loci, usually the gene symbol. Mouseovers display the disease with a
link to the CSpec, the VCEP panel with a link to the ClinGen VCEP page, and the current expert panel status.
Data Updates
Our programs check every day if ClinGen has an updated data file, and if so, update the track with the latest file.
Click the "Data Format" on this track documentation page to see when the track was last updated.
Data Access
The raw data can be explored interactively with the Table Browser,
or the Data Integrator. For automated analysis, the data may
be queried from our REST API. Please refer to our
mailing list archives
for questions, or our Data Access FAQ for more
information.
Data is also freely available on the ClinGen website
(gene-disease curation methods)
and FTP (dosage curations).
Credits
Thank you to ClinGen and NCBI, especially Erin Rooney Riggs, Christa Lese Martin, Tristan Nelson,
May Flowers, Scott Goehringer, and Phillip Weller for technical coordination and
consultation, and to Christopher Lee, Luis Nassar, and Anna Benet-Pages of the Genome
Browser team.
References
Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Martin
CL, Nussbaum RL et al.
ClinGen--the Clinical Genome Resource.
N Engl J Med. 2015 Jun 4;372(23):2235-42.
PMID: 26014595; PMC: PMC4474187
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E
et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus
recommendation of the American College of Medical Genetics and Genomics and the Association for
Molecular Pathology.
Genet Med. 2015 May;17(5):405-24.
PMID: 25741868; PMC: PMC4544753
Riggs ER, Church DM, Hanson K, Horner VL, Kaminsky EB, Kuhn RM, Wain KE, Williams ES, Aradhya S,
Kearney HM et al.
Towards an evidence-based process for the clinical interpretation of copy number variation.
Clin Genet. 2012 May;81(5):403-12.
PMID: 22097934; PMC: PMC5008023
Strande NT, Riggs ER, Buchanan AH, Ceyhan-Birsoy O, DiStefano M, Dwight SS, Goldstein J, Ghosh R,
Seifert BA, Sneddon TP et al.
Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed
by the Clinical Genome Resource.
Am J Hum Genet. 2017 Jun 1;100(6):895-906.
PMID: 28552198; PMC: PMC5473734
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