The ClinVar variation report

The ClinVar variation report displays information from submitters aggregated by each variant, rather than by the combination of variation-condition that is represented by the ClinVar accession ( e.g. RCV123456789.1).  The variation display makes it easier to review what has been submitted per simple or complex allele, combining data that submitters may have provided with different disease names.

ClinVar defines a variation as the set of sequence changes about which an interpretation has been submitted. In other words, a "variation" may represent a single variant, a compound heterozygote, or a complex haplotype.

This page explains the sections of the variation report. For a comparison of the variation report and the RCV record report, see our documentation comparing the displays .   If you want to view the record-specific RCV page, follow the link at the bottom of the Clinical significance section See supporting ClinVar records .

Title

The title represents the preferred name of the variation (Figure 1A).

  • For sequence variants within a gene, the name is constructed from the gene symbol and the HGVS expressions for the coding DNA and protein changes.
  • For sequence variants that are larger than a gene, the name is the HGVS expression for the genomic DNA change.
  • For structural variants, the name is constructed from the genome assembly name, cytogenetic location, genomic coordinates, and copy number, e.g.  GRCh38/hg38 1p31.1(chr1:71691191-72250907)x1

Variation ID

The Variation ID is a unique identifier for the set of sequence changes that were interpreted. In other words, if the variation report is for a haplotype defined by five SNPs, there is a single Variation ID that represents that combination of SNPs in cis. Each individual SNP is represented by an Allele ID (see the Allele Description section ).

Review Status / Stars

ClinVar reports the level of review supporting the assertion of clinical significance for the variation as review status. Stars provide a graphical representation of the review status on web pages. Please see our detailed description of the ClinVar review status .

Figure 1.  The title and allele sections of a variation report.

ClinVar variation report - title, interpretation, and allele sections

Interpretation

The section labeled Interpretation reports the overall clinical significance of a variation based on aggregating data from submitters (Figure 1B).  The details of what each submitter provided are listed in the Clinical Assertions tab (Figure 3).

In the the variation report, the value reported for clinical significance for Mendelian disorders is based on a 3-level scale.  This differs from what is reported on the ClinVar Record page, which uses the 5-level scale. Please see our detailed description of the representation of clinical significance in ClinVar and other variation resources at NCBI .

The values ClinVar and GTR use for clinical significance are maintained on GTR's ftp site.

ftp://ftp.ncbi.nlm.nih.gov/pub/GTR/standard_terms/Clinical_significance.txt

Number of submissions

Count of submissions for the variant. Note: this is the total count, not the count of submissions providing an interpretation. Thus the total number of submissions may be higher than suggested by the review status.

Condition(s)

The complete list of the conditions(s) that is/are being reported to have a relationship to this allele set, with links to databases with defining information about that condition.  Note that if the submitter(s) chose not to specify a condition, this section is blank. The details of what each submitter provided are in the Clinical Assertions tab.

See supporting ClinVar records

The link labeled See supporting ClinVar records goes to the related RCV records (representing the variant-condition).  If there is only one RCV accession related to the variant, you will be taken directly to that record. If there are multiple, a box opens up with the titles of the RCV records  that allows you to select the record to display.

Allele(s)

The allele section (Figure 1C) summarizes information that describes the allele. If the variant is specific to one gene, the gene symbol will be in the title. There is a separate section at the right (Figure 6) that reports all genes related to a variant.  The Allele ID is also reported; this identifier is for each individual nucleotide change in the set of variants that were interpreted. In other words, if the variation report is for interpretation of a haplotype defined by five SNPs, each SNP has its own Allele ID. The set of SNPs that make up the haplotype are represented by the Variation ID ( see the Title section ).

The allele section reports names and HGVS representations, with links to other data sources about the allele itself.  The data in the allele section may come from submitters, but may also be added by NCBI, especially when the allele can be placed on the genome.  Data usually provided by NCBI include:

  • HGVS expressions:
    • on the current and previous chromosome sequence (NC accession)
    • on the current NM/NP and RefSeqGene (NG)
    • on the version of the NM/NP annotated on the RefSeqGene (NG), if that is not the current version
    • provided by submitters NOTE : ClinVar does not currently list all possible HGVS expressions for a variant. The ones that are reported are selected according to the criteria above.
  • cytogenetic and genomic locations
  • the protein change, if applicable
  • links to related databases, such as dbSNP, dbVar, 1000 Genomes, Browser, and LSDBs (locus-specific databases)
  • GMAF , the global minor allele frequency calculated by the 1000 Genomes Project.
  • allele frequency, with source of the frequency data and the frequency of the stated allele
  • molecular consequence: a calculation of the effect of the sequence change.  If there are multiple splice forms for a gene, the consequence is reported for a representative RefSeq product per consequence. ClinVar calculates the predicted molecular consequence, but does not predict functional consequence. Functional consequence (e.g. quantitative effects on gene expression, alternative splicing) is based on experimental evidence and must be submitted.
  • Suspect : At least one line of evidence that variation calls in this region may be affected by paralogs or genome misassembly.

Assertion and evidence details

Clinical assertions tab

The overview of submissions made about each variant are separated into germline, somatic, and pharmacogenomic subsections to make it easier to distinguish among the three. Otherwise the table structure is identical. The data in the columns are taken directly from the submission, i.e. not aggregated by ClinVar.

Table 2. Columns in the Clinical assertion table

Column title Explanation
Clinical significance (Last evaluated) The value provided for clinical significance, with the date (optional) when the significance was last assessed. Interpretations from SCRP are submitted as individual reports which are aggregated by ClinVar. The most recent interpretation is reported on the ClinVar record; previous interpretations are available from the "History" link.
Review status (Assertion method) The review status of the submitted record.  Note in this example, there are data from ACMG (professional society), CFTR2 (an expert panel), and individual submitters. The method used to ascertain the clinical significance is reported as Assertion Method.
Collection method How the data were collected for submission.
Condition(s) (Mode of inheritance) The name of the condition about which the significance of the variant is being asserted.  Mode of inheritance is reported to indicate the mode of inheritance used to evaluate the significance. For pharmacogenomic variants, the condition for which the drug is used is also displayed.
Origin Origin of the variant.
Citations Usually links to PubMed.
Submitter (Last submitted) Name of the submitter, and the latest date that submitter provided information.
Submission accession The ClinVar accession assigned to the submission, including version number.

Figure 3. Display of a representative Clinical Assertions tab

the Clinial assertions tab from the ClinVar variation report

Summary evidence tab

The Summary evidence tab provides an overview of the evidence about a variant. The top row of the table aggregates data from all submitters to provide an overview of number of reported families, individuals, allele origin, ethnicities, and geographic origin. Subsequent rows provide a summary of the same categories for each submitter.

Figure 4. Display of a representative Summary evidence tab

Display of a summary evidence tab

Supporting Observations tab

The Supporting observations tab provides the specific evidence for each observation of a variant, including the number of reported individuals, allele origin, phenotypes, ethnicity, and geographic origin. An observation may represent a single individual or it may represent an aggregate count.

Figure 5. Display of a representative Supporting observations tab

Display of a supporting observations tab

Affected Genes

The Affected Genes section lists genes that overlap the location of the variant. For short variants, multiple genes may be listed because they overlap. For longer variants, multiple genes may be listed because the length spanned by the variant includes multiple genes.

There are several useful links in the Affected Genes section. These allow you to do the following:

Link name Function and uses
Table 4. Gene-related links
Gene Link to Gene. Useful to review multiple gene-related information, including other disorders known to be related to the gene.
OMIM Link to OMIM's record for the Gene
Variation Viewer Opens a gene-specific display in Variation Viewer. Useful to browse variation in a gene, configure your display to view other features that may affect interpretation of variation, and download results. Current defaults to GRCh37/hg19.
Haploinsufficiency Displays the current interpretation of haploinsufficiency for this gene from theClinGen Dosage Sensitivity Mapin a new window.
Triplosensitivity Displays the current interpretation of triplosensitivity for this gene from theClinGen Dosage Sensitivity Mapin a new window.
Search ClinVar for variants within Submits a new query to ClinVar for that gene, but restricted to variants that are within a gene.
Search ClinVar for variants including Submits a new query to ClinVar using the gene symbol.  Will inlcude structural variants.
Figure 6. Related data at the right of ClinVar's variation report.

Sections of related data on the right side of a ClinVar variation report

Variant frequency in dbGaP

This section indicates if the ClinVar variant is observed in dbGaP data. It provides both the count of submissions to dbGaP with the variant and the frequency of the variant in the database, not in the population. It reports two measures: called variants when the variant is observed in the set formally submitted with a dbGaP study, and potential variants when NCBI found the variant in aligned NGS with the dbGaP study, but we can take reads that were submitted with the study, align them to the genome, and see if that variant is observed in the reads.

Formally, called variants are submitted to dbGaP as subject genotypes and counted when a sample (subject genotype from VCF file) has at least one allele present; potential variants are computed by examination of any aligned next generation sequence for the sample that covers the position. A sample (SRA run accession) is counted when the allele is observed in at least 30% of the reads covering the position, and 10 or more clean reads (not flagged as artifact or PCR duplicate) cover the position.

Variant counts are updated on a monthly basis.

Browser Views

There are several types of links offered in the Browser Views section. These differ from those in the Affected Gene section in being focused on the variant, rather than including the complete gene.

Link Name Function and uses
Table 5. Links from Browser Views
RefSeqGene Opens a graphical display of the sequence of the RefSeqGene/LRG focused on the location of the variant.
GRCh38 Assembly Opens a  display in Variation Viewer focused on the location of the variant on GRCh38.
GRCh37 Assembly Opens a  display in Variation Viewer focused on the location of the variant on GRCh37.

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Last updated: 2018-05-31T17:55:02Z