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 Statement and Evidence Line 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 or Evidence Lines 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
   subjectVariant: clinvar/208366    # 'subjectVariant' specializes the VA Core 'subject' attribute, 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'
   objectCondition:           # 'objectCondition' specializes the VA Core 'object' attribute.
     id: clinvar.trait/939    # this is a MappableConcept object that represents the Condition, using names/codes from existing code systems
     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)
     primaryCoding:
       code: high
       system: ga4gh-gks-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
   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'
   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:            # reports the type of contribution that was made (here an evaluation activity)
       name: evaluated
     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:
       name: 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