The Gene Curation working group has included many substantial changes in the latest release of the Gene Curation SOP (Version 5). To better inform curators of these changes, the main points are summarized below and an annotated version of the SOP is included on this page:
gnomAD and Variant Minor Allele Frequencies (p 12): Further guidance is given on how to evaluate the pathogenicity of a variant before scoring it, including looking up minor allele frequencies in control databases, such as gnomAD.
Upgrading and Downgrading Variant Evidence Scores (p 13): The genetic evidence matrix provides a score range for variant evidence. In this section, guidance is given on when to score above and below the default suggested points per case for each variant type.
Segregation Scoring (p 15): In this segregation scoring update, the maximum segregation points are decreased from 7 to 3. Although the simplified LOD score calculation is the same, the required size to score autosomal recessive pedigrees has changed from two affecteds to three. Awarding points to LOD scores has also changed and we have added guidance for awarding different amounts of segregation points depending on the methods used to investigate the linkage interval. This section now provides a) instructions how to count segregations and calculate a simplified LOD score and b) how to evaluate the sequencing methods for the linkage interval and award points accordingly.
Experimental Evidence Matrix Wording (p 24): Although experimental evidence scoring has not changed, some clarifying wording changes were made to the experimental evidence summary matrix. More specifically, "Animal model" was changed to "Non-human model organism" to accommodate disease areas with non-animal model organisms (such as yeast), "Rescue" was extended to patient cells and humans to encompass studies such as enzyme replacement therapies, and "Rescue in an engineered equivalent" was changed to "Rescue in a cell culture model" for clarification.
Scoring Variant vs Experimental Evidence (p 27) Not all evidence supports the role of the gene in the disease. Therefore, the curator must carefully consider whether to count functional evidence in the experimental evidence section or in the case-level data section. Experimental evidence that does not directly support the role of the gene in the disease but indicates that the variant is damaging to the gene function can, instead, be used to increase points in the case-level data section. Further guidance on how to score some common general pieces of evidence is provided in this section.
Websites for curators (Appendix A, separate document on this page): A list of websites that may be useful for ClinGen gene curators.
Extended Experimental Evidence Examples (Appendix B, separate document on this page): The experimental evidence section in the SOP has been trimmed and extensive examples of each category of experimental evidence are available in the new Appendix B.