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A Brief Guide to Clinical Rare Disease Results

The aim of the Genomics England Tiering Project is to aid GLH evaluation of Rare Disease. When an initial analysis is complete, a small number of variants will be flagged to aid evaluation, i.e. those that are rare, predicted to have a functional consequence in the protein, and with a genotype and/or inheritance consistent with the patient’s disease, mode of inheritance and gene-phenotype association.

SNVs of potential relevance to the patient’s clinical presentation will be automatically categorised into the following tiers:

TIER 1

Includes, high impact variants (e.g. likely loss-of function) and de novo moderate impact variants (e.g. missense) within a curated list of genes available through PanelApp with sufficient evidence associating them with the patient’s phenotype(s). In the future it is anticipated Tier 1 will contain known pathogenic variants once a high confidence curated list has been generated.

TIER 2

Includes moderate impact variants (e.g. missense) within a curated list of genes available through PanelApp with sufficient evidence associating them with the patient’s phenotype(s).

TIER 3

Includes high and moderate impact variants outside of the curated list of genes associated with the patient’s phenotype(s). Although most tier 3 variants will NOT be pathogenic, sometimes the causal variant will lie within tier 3. This could occur because there is insufficient evidence to support the inclusion of the gene within the relevant panel(s) at the time of analysis, or because the relevant panel was not applied. All good quality, ‘PASS’ CNVs detected using a read depth based method (currently DRAGEN CNV algorithm) and of potential relevance to the patient’s clinical presentation will be automatically categorised into two tiers:

TIER A

Includes CNVs meeting one or both of the following criteria:

  • The CNV overlaps the pathogenic region in a panel applied to a participant, the overlap is above the threshold defined in PanelApp for that region, and the variant direction matches (i.e. Gain or Loss) that of the region in PanelApp. Please note, that the mode of inheritance is not considered. In practice in contrast to SNV and Indel (small variant) tiering, a single heterozygous CNV within or encompassing a biallelic gene will be tiered.
  • The CNV overlaps with the green gene in a panel applied to a participant. Any overlap in any gene region is considered. Please note that the mode of inheritance and variant direction (loss, gain) is not considered.

TIER Null

Includes all good quality, ‘PASS’ CNVs that do not satisfy any of the Tier A conditions.

Any remaining CNV's not considered 'Pass' quality are untiered

SVs detected from anomalously mapped read pairs (currently using the Manta algorithm) are not tiered, but are available in the variants tab for view.

All good quality, ‘PASS’ STRs detected using ExpansionHunter and of potential relevance to the patient’s clinical presentation will be automatically categorised into the following tiers:

  • Tier 1: The repeat-length for the locus is greater than or equal to the pathogenic threshold.

  • Tier 2: The repeat-length is greater than or equal to the threshold for normal alleles but less than the pathogenic threshold (defined in PanelApp).

  • Tier Null: Includes all good quality, ‘PASS’ STRs that do not satisfy any of the Tier 1 or Tier 2 conditions

STRs are only tiered for affected members of a family.

Reporting and interpretation of genomic results from Genomics England will necessarily be iterative and largely automated. Date-stamped genomics findings will be issued that summarise the current status of knowledge at the point the analysis was performed, but further additional findings may be issued for patients in future as the evidence-base grows.

If a patient has no Tier 1, 2 or A variants GLHs may wish to examine additional variants of potential interest (Tier 3, Tier Null or untiered). If an individual has consented to receive additional ‘looked-for’ findings, they will receive a separate Secondary Findings Report from Genomics England detailing known pathogenic variants in a short, specified list of actionable disease genes.

Any variants that are reported to patients by GLHs should be analytically and clinically validated. GLHs are not expected to validate negative findings unless there is a locally identified clinical need.

For additional information, please refer to the “Rare Disease Genome Analysis Guide’’

Last update: 2023-01-09