Using ClinVar as a Resource to Support Variant Interpretation

Abstract

ClinVar is a freely accessible, public archive of reports of the relationships among genomic variants and phenotypes. To facilitate evaluation of the clinical significance of each variant, ClinVar aggregates submissions of the same variant, displays supporting data from each submission, and determines if the submitted clinical interpretations are conflicting or concordant. The unit describes how to (1) identify sequence and structural variants of interest in ClinVar by multiple searching approaches, including Variation Viewer and (2) understand the display of submissions to ClinVar and the evidence supporting each interpretation. By following this protocol, ClinVar users will be able to learn how to incorporate the wealth of resources and knowledge in ClinVar into variant curation and interpretation.

Keywords: ClinVar; clinical genetics; data sharing; databases; variant interpretation.

Figure 1

The Variation Report presents all submissions referencing a given variant. The Variation Report displays the preferred variant name (A), overall review status (B), number of submissions (C), and list of unique asserted conditions (D).

Figure 2

The Record Report represents the result of aggregating data referencing the same variant relative to the same condition. The Record Report displays the asserted variant-condition combination (E), number of submissions for the variant-condition combination (F), and a hyperlink to the Variation Report (G).

Figure 3

ClinVar homepage displays a search bar and links to additional tools and resources.

Figure 4

Searching “c.1502A>G” in ClinVar returns five variants. The full HGVS expressions and affected genes are displayed in the Variation and Gene(s) columns, respectively.

Figure 5

All ClinVar variants in a given codon can be identified by searching with a single-letter amino acid code and codon position following by the wildcard character. Querying ClinVar with E501*[variant name] and BRAF identified five total BRAF variants at codon Glu501.

Figure 6

All ClinVar variants in a given genomic range can be identified by querying with chromosome number and start and stop genomic positions, such as 7[chr] AND 140400000:140700000[chrpos37]. Results can be filtered to only display large variants by selecting a Variant length filter on the left side of the search results page.

Figure 7

Variation Report page for variant NM_000138.4(FBN1):c.4786C>T (p.Arg1596Ter). The Variation Report page displays aggregate information regarding the variant review status (A), interpretation (B), alternative variant expressions (C), and impacted gene(s) (D). Assertions and evidence provided by each submitter are displayed in the Clinical assertions, Summary evidence, and Supporting observations tables at the bottom of the page (F).

Figure 8

Search results can be filtered for variants that meet specific criteria by using the annotations listed on the left side of the search result page. Filtering for all BRAF missense variants with a pathogenic assertion and multiple submitters with concordant interpretations returns 24 variants.

Figure 9

The Advanced search option can identify all variants in ClinVar that meet specific criteria by selecting the annotation type and indexed option by clicking Show index list and selecting desired option.

Figure 10

Variation Viewer set to display the desired exon in BRAF using the Gene and exon navigator field. The Sequence Viewer section displays the genomic region of interest, with additional tracks to display Genes, ClinVar Short Variations, dbVar ClinVar Large Variations, and dbSNP build 144 locations. The Variant table at the bottom of Variation Viewer displays all variants in the region of interest, which can be filter by the annotations in the Variant filters section.

Figure 11

Variation Viewer set to display ZEB2. Selecting a variant in the dbVar ClinGen Curated Dosage Sensitivity Map (nstd45) track displays the ClinGen curated clinical interpretation and associated phenotype for that variant and variant type. The Variant table section is set to only list variants in dbVar and ClinVar using the Variant filter annotations.

Figure 12

The Variant Review Status informs ClinVar users of the overall review status of a variant. The calculated variant review status value ranges from 0 to 4 stars.

Figure 13

The Summary evidence tab provides and overview of each submitter\'s evidence for the variant assertion, such as observation counts and variant interpretation summaries, if provided. The Supporting observations tab provides the specific evidence for each observation of a variant, including allele origin and phenotypes.

Figure 14

Clinical assertions and Supporting observations tabs for variant GRCh38/hg38 1q21.1(chr1:145635445-146009630)x1; VariantID: 160833