2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Applying the 2022 Guidelines for Non-Coding Variant Classification In a Large Rare Disease Cohort

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The document discusses the application of the 2022 Guidelines for Non-Coding Variant (NCV) classification in a large rare disease cohort. The study aimed to assess the impact of using the 2022 guidelines on NCV interpretation and classification. The researchers used a dataset of 160 NCVs, including canonical splice variants, non-canonical splice variants, UTR variants, and other non-coding gene variants. <br /><br />The results showed that the usage of the 2022 guidelines altered the ACMG evidence code usage and calculated pathogenicity for 30.6% of the NCVs assessed. Additionally, 5.6% of the NCVs had a shift in their overall ACMG classification category. The study also classified 78 NCVs that were absent from ClinVar at the time of analysis and reclassified 9 NCVs with conflicting pathogenicity interpretations.<br /><br />The researchers noted the value and challenges of implementing a classification framework specific to NCVs. They mentioned the plan to submit their variant interpretations to ClinVar, contributing to the openly accessible resource of NCVs classified using a standardized framework. The study emphasized the need for further calibration of evidence criteria and the use of functional assays and in silico predictors to advance NCV interpretation.<br /><br />Overall, the study highlights the importance of systematic frameworks for NCV classification in rare genetic diseases and provides insights into the application of the 2022 NCV guidelines in a large cohort.

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Presenting Author - Emily Groopman, MD, PhD; Co-Author - Broad Center for Mendelian Genomics, NA; Co-Author - Moriel Singer-Berk, MS; Co-Author - Nicola Whiffin, PhD; Co-Author - Jamie Ellingford, PhD; Co-Author - Samantha Baxter, MS, CGC; Co-Author - Heidi L. Rehm, PhD; Co-Author - Anne O’Donnell-Luria, MD, PhD;

Meta Tag

Bioinformatics

Genetic Testing

Genome sequencing

Genomic Methodologies

NextGen Sequencing

Sequencing

Co-Author Broad Center for Mendelian Genomics, NA

Co-Author Moriel Singer-Berk, MS

Co-Author Nicola Whiffin, PhD

Co-Author Jamie Ellingford, PhD

Co-Author Samantha Baxter, MS, CGC

Co-Author Heidi L. Rehm, PhD

Co-Author Anne O’Donnell-Luria, MD, PhD

Presenting Author Emily Groopman, MD, PhD

Keywords

2022 Guidelines

Non-Coding Variant

NCV classification

rare disease cohort

interpretation

classification

dataset

ACMG evidence code

pathogenicity

ClinVar