Version: 3.2.5

ClinVar

Overview

ClinVar is a freely accessible, public archive of reports of the relationships among human variations and phenotypes, with supporting evidence. ClinVar thus facilitates access to and communication about the relationships asserted between human variation and observed health status, and the history of that interpretation.

Publication

Melissa J Landrum, Jennifer M Lee, Mark Benson, Garth R Brown, Chen Chao, Shanmuga Chitipiralla, Baoshan Gu, Jennifer Hart, Douglas Hoffman, Wonhee Jang, Karen Karapetyan, Kenneth Katz, Chunlei Liu, Zenith Maddipatla, Adriana Malheiro, Kurt McDaniel, Michael Ovetsky, George Riley, George Zhou, J Bradley Holmes, Brandi L Kattman, Donna R Maglott, ClinVar: improving access to variant interpretations and supporting evidence, Nucleic Acids Research, 46, Issue D1, 4 January 2018, Pages D1062–D1067, https://doi.org/10.1093/nar/gkx1153

RCV File

Example

Here's a full RCV entry.

Parsing

In the following section, we discuss which field of the XML was used to extract information that is presented in the JSON output.

<ClinVarSet>
   <ReferenceClinVarAssertion>    
       <ClinVarAccession Acc="RCV000000001" Version="2">
</ClinVarSet>

The Acc and Version fields are merged to form the ID (RCV000000001.2)

LastUpdatedDate

<ClinVarSet>
   <ReferenceClinVarAssertion DateCreated="2012-08-13" DateLastUpdated="2016-02-17" ID="57604" >
</ClinVarSet>

Significance

<ClinVarSet>
   <ReferenceClinVarAssertion>
       <ClinicalSignificance DateLastEvaluated="1996-04-01">        
           <ReviewStatus>no assertion criteria provided</ReviewStatus>              
           <Description>Pathogenic</Description>            
       </ClinicalSignificance>
</ClinVarSet>

ReviewStatus

<ClinVarSet>
   <ReferenceClinVarAssertion>    
       <ClinicalSignificance DateLastEvaluated="1996-04-01">        
           <ReviewStatus>no assertion criteria provided</ReviewStatus>             
           <Description>Pathogenic</Description>            
       </ClinicalSignificance>
</ClinVarSet>

Phenotypes

<ReferenceClinVarAssertion>
   <TraitSet Type="Disease" ID="62">
       <Trait Type="Disease">
            <Name>
               <ElementValue Type="Preferred">Joubert syndrome 9</ElementValue>
            </Name>
        </Trait>
   </TraitSet>
</ReferenceClinVarAssertion>

We only use the field with Type="Preferred". Multiple phenotypes may be reported

Location and Variant Id

<ReferenceClinVarAssertion>
<GenotypeSet Type="CompoundHeterozygote" ID="424709">
   <MeasureSet Type="Variant" ID="81">
       <Measure Type="single nucleotide variant" ID="15120">
        <SequenceLocation Assembly="GRCh38" AssemblyAccessionVersion="GCF_000001405.38"  
          AssemblyStatus="current" Chr="10" Accession="NC_000010.11" start="89222510"  
          stop="89222510" display_start="89222510" display_stop="89222510" variantLength="1"  
          positionVCF="89222510" referenceAlleleVCF="C" alternateAlleleVCF="T"/>  
        <SequenceLocation Assembly="GRCh37" AssemblyAccessionVersion="GCF_000001405.25"  
          AssemblyStatus="previous" Chr="10" Accession="NC_000010.10" start="90982267"  
          stop="90982267" display_start="90982267" display_stop="90982267" variantLength="1"  
          positionVCF="90982267" referenceAlleleVCF="C" alternateAlleleVCF="T"/>
       </Measure>
   </MeasureSet>
 </GenotypeSet>
</ReferenceClinVarAssertion>

The variant position is extracted from the fields for their respective assemblies.
Updated records contain positionVCF, referenceAlleleVCF and alternateAlleleVCF fields and when present, we use them to create the variant.
For older records, since "start' and "stop" fields are not always available, we use the "display_start" and "display_end" fields.
If a required allele is not available, we extract it from the reference sequence.
Only variants having a dbSNP id are extracted.
Note that a ClinVar accession may have multiple variants associated with it (possible in different locations)
VariantId is extracted from the MeasureSet attributes.

MedGen, OMIM, Orphanet IDs

<ReferenceClinVarAssertion>
   <TraitSet Type="Disease" ID="175">
       <Trait ID="3036" Type="Disease">
           <XRef ID="C0086651" DB="MedGen"/>
           <XRef ID="309297" DB="Orphanet"/>
           <XRef ID="582" DB="Orphanet"/>
           <XRef Type="MIM" ID="253000" DB="OMIM"/>
       </Trait>
   </TraitSet>
</ReferenceClinVarAssertion>

AlleleOrigins

<ClinVarAssertion>
     <Origin>germline</Origin>
</ClinVarAssertion>

We only extract all Allele Origins from Submissions (SCV) entries.

PubMedIds

<ClinVarAssertion>
   <ClinicalSignificance DateLastEvaluated="1996-04-01">
       <Citation Type="general">
           <ID Source="PubMed">12114475</ID>
       </Citation>
   </ClinicalSignificance>
   <AttributeSet>
       <Attribute Type="AssertionMethod">LMM Criteria</Attribute>
       <Citation>
            <ID Source="PubMed">24033266</ID>
       </Citation>
   </AttributeSet>
   <ObservedIn>
       <ObservedData ID="9727445">
           <Citation Type="general">
               <ID Source="PubMed">9113933</ID>
           </Citation>
       </ObservedData>
   </ObservedIn>
   <Citation Type="general">
       <ID Source="PubMed">23757202</ID>
   </Citation>
</ClinVarAssertion>

We only extract all Pubmed Ids from Submissions (SCV) entries.

Parsing Significance

Extracting significance(s) may involve parsing multiple fields. Take the following snippets into consideration.

<ClinicalSignificance DateLastEvaluated="1996-04-01">
    <ReviewStatus>no assertion criteria provided</ReviewStatus>
    <Description>Pathogenic</Description>
</ClinicalSignificance>

<ClinicalSignificance DateLastEvaluated="2016-10-13">
    <ReviewStatus>criteria provided, multiple submitters, no conflicts</ReviewStatus>
    <Description>Pathogenic/Likely pathogenic</Description>
</ClinicalSignificance>

<ClinicalSignificance DateLastEvaluated="2012-06-07">
    <ReviewStatus>no assertion criteria provided</ReviewStatus>
    <Description>Conflicting interpretations of pathogenicity</Description>
    <Explanation DataSource="ClinVar" Type="public">Pathogenic(1);Uncertain significance(1)</Explanation>
</ClinicalSignificance>

Given the evidence, we converted the significance field into an array of strings which may be parsed out of the Descriptions or Explanation fields.

Varying Delimiters

The delimiters in each field may vary. Currently, the delimiters for Description are , and /. The delimiters for Explanation are ; and /.

Known Issues

The XML file contains ~1k more entries (out of 162K) than the VCF file
The XML file does not have a field indicating that a record is associated with the reference base - something that was present in VCF
The XML file contains entries (e.g. RCV000016645 version=1) which have IUPAC ambiguous bases ("R", "Y", "H", etc.) as their alternate allele

Download URL

ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/xml/ClinVarFullRelease_00-latest.xml.gz

JSON Output

"clinvar":[
   {
      "id":"RCV000030258.4",
      "reviewStatus":"reviewed by expert panel",
      "alleleOrigins":[
         "germline"
      ],
      "refAllele":"G",
      "altAllele":"A",
      "phenotypes":[
         "Lynch syndrome"
      ],
      "medGenIds":[
         "C1333990"
      ],
      "omimIds":[
         "120435"
      ],
      "significance":[
         "benign"
      ],
      "lastUpdatedDate":"2017-05-01",
      "isAlleleSpecific":true
   }
]

Field	Type	Notes
id	string	ClinVar ID
reviewStatus	string	see possible values below
alleleOrigins	string array	see possible values below
refAllele	string
altAllele	string
phenotypes	string array
medGenIds	string array	MedGen IDs
omimIds	string array	OMIM IDs
orphanetIds	string array	Orphanet IDs
significance	string array	see possible values below
lastUpdatedDate	string	yyyy-MM-dd
pubMedIds	string array	PubMed IDs
isAlleleSpecific	bool	true when the current variant alternate allele matches the ClinVar alternate allele

reviewStatus:

no assertion provided
no assertion criteria provided
criteria provided, single submitter
practice guideline
classified by multiple submitters
criteria provided, conflicting interpretations
criteria provided, multiple submitters, no conflicts
no interpretation for the single variant

alleleOrigins:

unknown
other
germline
somatic
inherited
paternal
maternal
de-novo
biparental
uniparental
not-tested
tested-inconclusive

significance:

uncertain significance
not provided
benign
likely benign
likely pathogenic
pathogenic
drug response
histocompatibility
association
risk factor
protective
affects
conflicting data from submitters
other
no interpretation for the single variant
conflicting interpretations of pathogenicity

Overview​

Publication

RCV File​

Example​

Parsing​

Parsing Significance​

Varying Delimiters

Known Issues​

Known Issues

Download URL​

JSON Output​

Overview

RCV File

Example

Parsing

Parsing Significance

Known Issues

Download URL

JSON Output