Update to the PVS1 ACMG Rule

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.

• For example: chr1-171621616-G-A (MYOC:p.R46*) is now classified as VUS instead of Pathogenic.

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

• https://varsome.com/about/acmg-implementation/

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:

• https://api.varsome.com/lookup/gene/MS4A1/hg19?add-all-data=1&exclude-source-databases=exac-genes