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Variants with pathogenic/likely pathogenic disease associations

The population frequency filter (Criterion 2) or predicted function coding impact filter (Criterion 3) may result in potentially diagnostic variants with known pathogenic/likely pathogenic associations not being prioritised, e.g. if they are known to be pathogenic but above allele frequency threshold used during variant tiering.

The addition of this criterion enables data from external sources to be used to prioritise variants with known pathogenic/likely pathogenic associations that would not otherwise be prioritised. This also enables variants that do not occur in transcripts with a considered biotype (see Criterion 3) to be prioritised.

ClinVar

ClinVar aggregates information about genomic variation and its relationship to human health. An individual submission to ClinVar asserting a relationship between a variant and condition are represented by a SCV record. All submissions about the same variant are aggregated into a VCV record.

A variant passes Criterion 6 if:

  1. The variant, or a variant with the same HGVSp as the variant, has a VCV record with a clinical significance that is one of:

    • Pathogenic
    • Likely pathogenic
    • Conflicting interpretations of pathogenicity

  2. The variant, or a variant with the same HGVSp as the variant, has a VCV record with review status that is one of

    • Practice guideline
    • Reviewed by expert panel
    • Criteria provided, multiple submitters, no conflicts
    • Criteria provided, conflicting interpretations1
    • Criteria provided, single submitter
    • No assertion criteria provided

  3. The variant must have a population frequency in the custom Genomics England frequencies GEL_aggCOVID_V4.2-20220117 dataset less than 0.05.

Clinical Variant Ark (CVA)

CVA is a Genomics England database which stores classifications assigned to genomic variants for samples processed by Genomics England bioinformatics pipelines.

A variant passes Criterion 6 if:

  1. The variant has at least one pathogenic or likely pathogenic classification in CVA at the time of interpretation, or

  2. A variant with the same protein change, based on HGVSp annotation for the same transcript, has at least one pathogenic or likely pathogenic classification in CVA at the time of interpretation

Note

HGVSp annotations are only available for variants classified in cases run following the Izar release in March 2023

Note

Variant classifications in CVA are continually updated as GMS referrals are reviewed and findings returned. A variant with no pathogenic or likely pathogenic classifications in CVA at the point of interpretation will not pass criterion 6 for CVA even if the variant is subsequently classified as pathogenic or likely pathogenic before being reviewed. However, the variant will display the current CVA classification in the Interpretation Portal.

  1. Variants with a review status of “criteria provided, conflicting interpretations” must have at least one associated SCV record with a pathogenic/likely pathogenic assertion. ↩