Dataset Information

ClinGen expert clinical validity curation of 164 hearing loss gene-disease pairs.

ABSTRACT:

Purpose

Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene-disease relationships. The Clinical Genome Resource (ClinGen) has developed a semiquantitative framework to assign clinical validity to gene-disease relationships.

Methods

The ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene-disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss.

Results

The final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website ( https://search.clinicalgenome.org/kb/gene-validity ).

Conclusion

This gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.

SUBMITTER: DiStefano MT

PROVIDER: S-EPMC7280024 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

ClinGen expert clinical validity curation of 164 hearing loss gene-disease pairs.

DiStefano Marina T MT Hemphill Sarah E SE Oza Andrea M AM Siegert Rebecca K RK Grant Andrew R AR Hughes Madeline Y MY Cushman Brandon J BJ Azaiez Hela H Booth Kevin T KT Chapin Alex A Duzkale Hatice H Matsunaga Tatsuo T Shen Jun J Zhang Wenying W Kenna Margaret M Schimmenti Lisa A LA Tekin Mustafa M Rehm Heidi L HL Tayoun Ahmad N Abou ANA Amr Sami S SS

Genetics in medicine : official journal of the American College of Medical Genetics 20190321 10

<h4>Purpose</h4>Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene-disease relationships. The Clinical Genome Resource (ClinGen) has developed a semiquantitative framework to assign clinical validity to gene-disease relationships.<h4>Methods</h4>The ClinGen Hearing Loss Gene Curation Expert Panel (HL G ...[more]

PMID: 30894701

Similar Datasets

Project description:BACKGROUND:The 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that "well-established" functional studies can be used as evidence in variant classification. These guidelines articulated key attributes of functional data, including that assays should reflect the biological environment and be analytically sound; however, details of how to evaluate these attributes were left to expert judgment. The Clinical Genome Resource (ClinGen) designates Variant Curation Expert Panels (VCEPs) in specific disease areas to make gene-centric specifications to the ACMG/AMP guidelines, including more specific definitions of appropriate functional assays. We set out to evaluate the existing VCEP guidelines for functional assays. METHODS:We evaluated the functional criteria (PS3/BS3) of six VCEPs (CDH1, Hearing Loss, Inherited Cardiomyopathy-MYH7, PAH, PTEN, RASopathy). We then established criteria for evaluating functional studies based on disease mechanism, general class of assay, and the characteristics of specific assay instances described in the primary literature. Using these criteria, we extensively curated assay instances cited by each VCEP in their pilot variant classification to analyze VCEP recommendations and their use in the interpretation of functional studies. RESULTS:Unsurprisingly, our analysis highlighted the breadth of VCEP-approved assays, reflecting the diversity of disease mechanisms among VCEPs. We also noted substantial variability between VCEPs in the method used to select these assays and in the approach used to specify strength modifications, as well as differences in suggested validation parameters. Importantly, we observed discrepancies between the parameters VCEPs specified as required for approved assay instances and the fulfillment of these requirements in the individual assays cited in pilot variant interpretation. CONCLUSIONS:Interpretation of the intricacies of functional assays often requires expert-level knowledge of the gene and disease, and current VCEP recommendations for functional assay evidence are a useful tool to improve the accessibility of functional data by providing a starting point for curators to identify approved functional assays and key metrics. However, our analysis suggests that further guidance is needed to standardize this process and ensure consistency in the application of functional evidence.

Dataset Information

ClinGen expert clinical validity curation of 164 hearing loss gene-disease pairs.

Purpose

Methods

Results

Conclusion

Publications

ClinGen expert clinical validity curation of 164 hearing loss gene-disease pairs.

Similar Datasets

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