ClinGen Track Settings
 
ClinGen curation activities (Dosage Sensitivity and Gene-Disease Validity)   (All Phenotype and Literature tracks)

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 ClinGen Haploinsufficiency  ClinGen Dosage Sensitivity Map - Haploinsufficiency   Schema 
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 ClinGen Triplosensitivity  ClinGen Dosage Sensitivity Map - Triplosensitivity   Schema 
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 ClinGen Validity  ClinGen Gene-Disease Validity Classification   Schema 

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.

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.

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

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