ACMG Variant Pathogenicity Statement Example

Description:

• The Pathogenicity Statement data below adds instructive annotations to this Simple Test Fixtures Example from ClinGen’s “ClinVar-GKS” implementation of the Variant Pathogenicity Statement (ACMG 2015) Profile.

• The annotations are intended to help readers better understand the structure, semantics, and utility of VA-Spec models.

• The example itself covers a subset of data from the ClinVar SCV000778434.1 record - which reports that “the KCNQ4 variant NM_004700.4:c.803CCT[1] is pathogenic for Autosomal dominant nonsyndromic hearing loss 2A”.

• Note that the data below omits a full representation of the CategoricalVariation that is the subject of the Statement - as this is the remit of the CatVRS specification.

Data:

Note

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

SCV000778434.1:
 id: SCV000778434.1
 type: Statement              # Formal type in the model is 'Statement', but the data aligns with the "Variant Pathogenicity Statement (ACMG 2015)" Community Profile.
 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: definitive         # the code here is a term based on language used in the ACMG guidelines, as ACMG does not provide a formal code system for this
     system: ACMG Guidelines, 2015
 classification:              # holds a MappableConcept reporting the final ACMG classification of the subject variant  to be 'pathogenic'
   primaryCoding:
     code: pathogenic         # the code here is a term based on language in the ACMG guidelines, as ACMG does not provide a formal code system for this
     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 guidelines followed in generating 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
     pmid: 25741868
     name: ACMG Guidelines, 2015