---
title: Update to the PVS1 ACMG Rule
description: Rule PVS1 has been updated to use updated Loss-of-Function prediction from GnomAD instead of ExAC.
---

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# Update to the PVS1 ACMG Rule

 By [Charles Chapple](https://updates.varsome.com/en/author/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](https://varsome.com/about/acmg-implementation/#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\*)](https://varsome.com/variant/hg19/chr1-171621616-G-A) is now classified as VUS instead of Pathogenic.

Importantly, the gene LOF prediction from GnomAD now identifies [PVS1](https://varsome.com/about/acmg-implementation/#pvs1) variants in some genes for which there are no clinically reported pathogenic variants.

- For example: [chr19-8386415-A-G](https://varsome.com/variant/hg19/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/](https://varsome.com/about/acmg-implementation/)

### VarSome API

This change will be automatically reflected in the data returned by the [VarSome API](https://varsome.com/information/varsome-api-info/) 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

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