Dataset Information

Reevaluating the Mutation Classification in Genetic Studies of Bradycardia Using ACMG/AMP Variant Classification Framework.

ABSTRACT: Purpose:Next-generation sequencing (NGS) has become more accessible, leading to an increasing number of genetic studies of familial bradycardia being reported. However, most of the variants lack full evaluation. The relationship between genetic factors and bradycardia should be summarized and reevaluated. Methods:We summarized genetic studies published in the PubMed database from 2008/1/1 to 2019/9/1 and used the ACMG/AMP classification framework to analyze related sequence variants. Results:We identified 88 articles, 99 sequence variants, and 34 genes after searching the PubMed database and classified ABCC9, ACTN2, CACNA1C, DES, HCN4, KCNQ1, KCNH2, LMNA, MECP2, LAMP2, NPPA, SCN5A, and TRPM4 as high-priority genes causing familial bradycardia. Most mutated genes have been reported as having multiple clinical manifestations. Conclusions:For patients with familial CCD, 13 high-priority genes are recommended for evaluation. For genetic studies, variants should be carefully evaluated using the ACMG/AMP variant classification framework before publication.

SUBMITTER: Cheng L

PROVIDER: S-EPMC7061116 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Reevaluating the Mutation Classification in Genetic Studies of Bradycardia Using ACMG/AMP Variant Classification Framework.

Cheng Liting L Li Xiaoyan X Zhao Lin L Wang Zefeng Z Zhang Junmeng J Liang Zhuo Z Wu Yongquan Y

International journal of genomics 20200225

<h4>Purpose</h4>Next-generation sequencing (NGS) has become more accessible, leading to an increasing number of genetic studies of familial bradycardia being reported. However, most of the variants lack full evaluation. The relationship between genetic factors and bradycardia should be summarized and reevaluated.<h4>Methods</h4>We summarized genetic studies published in the PubMed database from 2008/1/1 to 2019/9/1 and used the ACMG/AMP classification framework to analyze related sequence varian ...[more]

PMID: 32211440

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Project description:BACKGROUND:The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for "well-established" functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation. METHODS:The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated the odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development. RESULTS:The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are as follows: (1) define the disease mechanism, (2) evaluate the applicability of general classes of assays used in the field, (3) evaluate the validity of specific instances of assays, and (4) apply evidence to individual variant interpretation. We found that a minimum of 11 total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis. CONCLUSIONS:The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.

Dataset Information

Reevaluating the Mutation Classification in Genetic Studies of Bradycardia Using ACMG/AMP Variant Classification Framework.

Publications

Reevaluating the Mutation Classification in Genetic Studies of Bradycardia Using ACMG/AMP Variant Classification Framework.

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