Update to the PVS1 ACMG Rule

By Charles Chapple on October, 2 2020

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Charles Chapple

Head of Bioinformatics

We would like to draw your attention to the following improvement to VarSome’s automated ACMG classification:

  • Rule PVS1 has been updated to use Loss-of-Function prediction from GnomAD instead of ExAC.
  • Only LOF variants are considered when tallying the number of known pathogenic variants in the gene.

This affects a few genes such as MYOC for which LOF is not disease causing, although there are many pathogenic missense variants.

Importantly, the gene LOF prediction from GnomAD now identifies PVS1 variants in some genes for which there are no clinically reported pathogenic variants.

  • For example: chr19-8386415-A-G (RPS28:p.M1V) now triggers PVS1 and is classified as Pathogenic.

VarSome's ACMG Documentation

VarSome API

This change will be automatically reflected in the data returned by the VarSome API variant lookups if the add-ACMG-annotation=1 GET parameter is set on the request.

GnomAD Genes data are also available on gene related lookups along the ExAC Genes database if the add-all-data=1 GET parameter is set on the request.

If you wish to discard the ExAC Genes database (which is replaced by the GnomAD Genes database) you need to set the exclude-source-databases GET parameter on the request:


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