Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion

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.

Keywords: ACMG/AMP; ClinGen; PVS1; loss of function; variant interpretation.

Figure 1.. PVS1 decision tree.

Refer to text for detailed description. NMD, nonsense-mediated decay; LoF, loss of function. a, This criterion should not be applied in combination with in silico splicing predictions (PP3). Additionally, splice site variants must have no detectable nearby (+/− 20 nts) strong consensus splice sequence that may reconstitute in-frame splicing. b, NMD prediction based on the premature termination codon not occurring in the 3’ most exon or the 3’-most 50 bp of the penultimate exon. c, Relevant domain indicated by experimental evidence proving a critical role of the domain and/or presence of non-truncating pathogenic variants in the region. d, For a full gene deletion of a known haploinsufficient gene, a Pathogenic classification is warranted (in the absence of conflicting data) even though application of PVS1 alone would not reach a Pathogenic classification using the combining rules in Richards et al 2017.