The latest update to Mastermind has integrated ClinVar, a public database of clinically observed variants and their pathogenicity interpretations by the clinical labs that submitted the variants. This can often serve as a quick jumping off point for deciding to further investigate a given variant based on the evidence provided in Mastermind.

Evidence for ClinVar variants

Having ClinVar integrated directly into Mastermind means you can see primary evidence from the medical literature for the interpretations in ClinVar. Simply search Mastermind as you normally would, and if a variant exists in ClinVar, it will show up above the literature results in Mastermind.

Search ClinVar by cDNA

With Mastermind, you can easily search variants by cDNA nomenclature even if you’re not sure of the transcript identifier. For example, searching ALPL:c.1091_1092insGCAG will automatically return the ClinVar record for the same protein frameshift effect of p.Ser364fs, even though the cDNA change in the ClinVar record is described slightly differently.

Searching this variant in ClinVar returns no records, making it easy to miss this likely pathogenic variant as interpreted in ClinVar.

Search ClinVar by protein changes

Searching by protein effect directly is easy as well. For example, searching Mastermind for a nonsense variant shows the ClinVar interpretation with the Mastermind citations. The type-ahead suggestions in Mastermind, which validate transcripts and normalize nomenclatures, make it easy to enter variants with confidence. In ClinVar, entering p.Y39Y will yield no results while p.Y39= will show the applicable record.

Search ClinVar by genomic coordinates

Mastermind allows searching by genomic coordinates directly using either GRCh37 (hg18) or GRCh38 (hg19) coordinates, and shows results for variants mapping across multiple transcripts. Searching NC_000001.10:g.21887174T>C returns the same record as above without needing to remember the gene or transcript onto which the variant maps.

Search ClinVar by rsID

Searching by dbSNP rsIDs likewise will show any matching ClinVar records along with any citations in the literature regardless of nomenclature used by authors, even when the rsID itself may not be mentioned at all in the paper. Similarly to the genomic coordinate search, searching rs121918013 returns the appropriate variant without needing to look up the affected gene(s).

Search ClinVar by variant types

Finally, a feature unique to Mastermind is the ability to search variants by effect, even when the effect doesn’t map directly to a specific protein nomenclature. For example, Mastermind makes it easy to search for any variant in the donor-side splice region of a given codon. In addition to returning all variant citations affecting this splice region, Mastermind will now return all ClinVar records mapping to variants in this region as well. In this example, searching ALPL:G61srd finds three ClinVar records, from which you can select to quickly toggle between in the drop-down under the ClinVar tab.

See more about the non-coding groupings which can be searched with special nomenclatures in our Non-Coding Variant Precision and Prioritization blog post.

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