ArticleHuman mutation2018
Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.
Article in Human mutation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 597 papers, 1 of them a synthesis that pooled it.
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Who cites it
597 citing papers in PubMed, 1 synthesis or guideline pooled it.
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- Pathogenicity assessment of genetic variants in reproductive disorders.Journal of assisted reproduction and genetics · 2026Review
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- Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.Human genetics · 2026Article
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- From Guidelines to Practice: Pilot Implementation and Analytical Boundaries of a Focused ADPKD-Spectrum Gene Panel.Diagnostics (Basel, Switzerland) · 2026Article
- A Genotype-Phenotype Analysis of Four Chinese Children Carrying Distinct Pathogenic Variants in theGenes · 2026Article
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537 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors.
Funding
Abstract
The 2015 ACMG/AMP sequence variant interpretation guideline provided a framework for classifying variants based on several benign and pathogenic evidence criteria, including a pathogenic criterion (PVS1) for predicted loss of function variants. However, the guideline did not elaborate on specific considerations for the different types of loss of function variants, nor did it provide decision-making pathways assimilating information about variant type, its location, or any additional evidence for the likelihood of a true null effect. Furthermore, this guideline did not take into account the relative strengths for each evidence type and the final outcome of their combinations with respect to PVS1 strength. Finally, criteria specifying the genes for which PVS1 can be applied are still missing. Here, as part of the ClinGen Sequence Variant Interpretation (SVI) Workgroup's goal of refining ACMG/AMP criteria, we provide recommendations for applying the PVS1 criterion using detailed guidance addressing the above-mentioned gaps. Evaluation of the refined criterion by seven disease-specific groups using heterogeneous types of loss of function variants (n = 56) showed 89% agreement with the new recommendation, while discrepancies in six variants (11%) were appropriately due to disease-specific refinements. Our recommendations will facilitate consistent and accurate interpretation of predicted loss of function variants.
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