Custom Variant Pathogenicity Statement Example

Building Custom Statement Models:

  • Representation of a particular type of Statement or Evidence Line using the VA-Spec does not always require a Profile to be specifically defined for it.

  • The Community Profiles included in version 1.0 of the VA-Spec are there to support data providers pursuing strict alignment with a particular community guidelines.

  • Implementers who do not seek such alignment can build their own schema for Statements to report on any of the knowledge types specified in VA Base Proposition profiles.

  • For example, starting with the core Statement<Statement> class, simply bind its proposition attribute to the relevant Proposition base profile, and the permissive core Statement attributes will not impose community-specific constraints around representation of additional information about the Statement (e.g. strength, provenance, source documents, etc).

Example Description:

  • The example below represents the same ClinVar-based Variant Pathogenicity Statement as in this Simple Test Fixtures Example, but does not conform to the ACMG 2015 Community Profile for this statement type.

  • Instead, the schema uses the core Statement class with in a base Variant Pathogenicity Proposition, and the looser constraints on the core class to allow use of the implementers preferred vocabularies for capturing things like Statement strength and classification.

  • Annotations in the example point out where the implementers preferred codes are used instead of ACMG-based terms.

Data:

Note

Comments in the example below will be easier to view in the Custom Pathogenicity Statement Example Source Yaml, which affords the option of a wider browser window.

SCV000778434.1:
 id: SCV000778434.1
 type: Statement
 proposition:                 # a Proposition object captures the possible fact assessed by the Statement, using a subject, predicate, object, qualifier (SPOQ) semantic modeling pattern.
   id: ex:Proposition001      # the proposition here is that "NM_004700.4:c.803CCT[1] is causal for AD nonsyndromic hearing loss 2A"
   type: VariantPathogenicityProposition
   subject: clinvar/208366    # the 'subject' of the Proposition, narrowed to a variant, and holds a CatVRS 'Categorical Variant' whose full representation is not shown here.
   predicate: isCausalFor     # the predicate for this Statement profile is fixed at 'isCausalFor'
   object:           # the 'object' of the Proposition, narrowed to a Condition.
     id: clinvar.trait/939    # this is a MappableConcept object that represents the Condition, using names/codes from existing code systems
     type: MappableConcept
     conceptType: Disease
     name: Autosomal dominant nonsyndromic hearing loss 2A    # the name for the concept as assigned by the data provider
     primaryCoding:           # holds a Coding object, where the concept is defined in the 'code' or 'name' field
       code: C2677637         # the code from the MedGen terminology for AD nonsyndromic hearing loss 2A
       system: https://www.ncbi.nlm.nih.gov/medgen/
       iris:
         - http://identifiers.org/medgen/C2677637
   penetranceQualifier:       # holds a MappableConcept that reports qualifying penetrance information about the object condition (here, that the statement holds for high penetrance AD hearing loss)
     type: MappableConcept
     primaryCoding:
       code: high
       system: ga4gh-gkm-term:pathogenicity-penetrance-qualifier   # code system here is a locally defined placeholder, until we formalize terminological standards for use in the VA-Spec
     name: high
 direction: supports          # an enumerated string that indicates the Statement 'supports' the Proposition as true
 strength:                    # holds a MappableConcept reporting that confidence/evidence for this stated support
   type: MappableConcept
   primaryCoding:
     code: established        # the code here based on a term used in the implementers preferred guidelines or application (as opposed to ACMG terminological conventions)
     system: Implementer System 1
 classification:                     # holds a MappableConcept reporting the final classification of the subject variant to be 'disease-causing'
   type: MappableConcept
   primaryCoding:
     code: disease-causing    # the code here based on a term used in the implementers preferred guidelines or application (as opposed to ACMG terminological conventions)
     system: ACMG Guidelines, 2015
 contributions:               # a list of Contribution objects, each describing how an agent contributed to the Statement
   - type: Contribution
     contributor:             # reports who made this contribution
       id: clinvar.submitter/500139
       type: Agent
       name: ClinVar Staff, National Center for Biotechnology Information (NCBI)
     activityType: evaluated  # reports the type of contribution that was made (here an evaluation activity)
     date: '2015-08-20'       # reports when this contribution was performed
   - type: Contribution
     contributor:
       id: clinvar.submitter/500139
       type: Agent
       name: ClinVar Staff, National Center for Biotechnology Information (NCBI)
     activityType: submitted
     date: '2018-06-12'
 specifiedBy:                 # holds a Method object describing the implementers guidelines and terminology for recording the knowledge reported in the Statement
   type: Method
   reportedIn:                # a document that describes the Method (this is all we are given about this Method in the source data)
     type: Document
     name: Alternate Guidelines and Terminology for Variant Pathogenicity Classification