Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel

Kathryn P Burdon; Patricia Graham; Johanna Hadler; John D Hulleman; Francesca Pasutto; Erin A Boese; Jamie E Craig; John H Fingert; Alex W Hewitt; Owen M Siggs; Kristina Whisenhunt; Terri L Young; David A Mackey; Andrew Dubowsky; Emmanuelle Souzeau

doi:10.1002/humu.24482

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Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel

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Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel

Kathryn P Burdon, Patricia Graham, Johanna Hadler, John D Hulleman, Francesca Pasutto, Erin A Boese, Jamie E Craig, John H Fingert, Alex W Hewitt, Owen M Siggs, …

Human mutation, Vol.43(12), pp.2170-2186

10/11/2022

DOI: 10.1002/humu.24482

PMCID: PMC9771967

PMID: 36217948

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Abstract

The standardization of variant curation criteria is essential for accurate interpretation of genetic results and clinical care of patients. The variant curation guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 are widely used but are not gene specific. To address this issue, the Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEP) have been tasked with developing gene-specific variant curation guidelines. The Glaucoma VCEP was created to develop rule specifications for genes associated with primary glaucoma, including myocilin (MYOC), the most common cause of Mendelian glaucoma. Of the 28 ACMG/AMP criteria, the Glaucoma VCEP adapted 15 rules to MYOC and determined 13 rules not applicable. Key specifications included determining minor allele frequency thresholds, developing an approach to counting probands and segregations, and reviewing functional assays. The rules were piloted on 81 variants and led to a change in classification in 40% of those that were classified in ClinVar, with functional evidence influencing the classification of 18 variants. The standardized variant curation guidelines for MYOC provide a framework for the consistent application of the rules between laboratories, to improve MYOC genetic testing in the management of glaucoma.

Details

Title: Subtitle: Specifications of the ACMG/AMP variant curation guidelines for myocilin: Recommendations from the clingen glaucoma expert panel
Creators: Kathryn P Burdon - Menzies Research Institute
Patricia Graham - Menzies Research Institute
Johanna Hadler - Flinders Medical Centre
John D Hulleman - The University of Texas Southwestern Medical Center
Francesca Pasutto - University of Erlangen-Nuremberg
Erin A Boese - University of Iowa
Jamie E Craig - Flinders Medical Centre
John H Fingert - University of Iowa
Alex W Hewitt - Menzies Research Institute
Owen M Siggs - Flinders Medical Centre
Kristina Whisenhunt - Visual Sciences
Terri L Young - Visual Sciences
David A Mackey - Lions Eye Institute
Andrew Dubowsky - South Australia Pathology
Emmanuelle Souzeau - Flinders Medical Centre
Resource Type: Journal article
Publication Details: Human mutation, Vol.43(12), pp.2170-2186
DOI: 10.1002/humu.24482
PMID: 36217948
PMCID: PMC9771967
NLM abbreviation: Hum Mutat
ISSN: 1059-7794
eISSN: 1098-1004
Grant note: DOI: 10.13039/100009727, name: Hospital Research Foundation; DOI: 10.13039/100001818, name: Research to Prevent Blindness; DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/501100000925, name: National Health and Medical Research Council
Language: English
Date published: 10/11/2022
Academic Unit: Ophthalmology and Visual Sciences
Record Identifier: 9984306258202771

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