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Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Classifications in Malignant Hyperthermia Susceptibility
PURPOSE: As a ClinGen Expert Panel (EP) we set out to adapt the ACMG pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly-inherited malignant hyperthermia (MH). METHODS: We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263483/ https://www.ncbi.nlm.nih.gov/pubmed/33767344 http://dx.doi.org/10.1038/s41436-021-01125-w |
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author | Johnston, Jennifer J. Dirksen, Robert T. Girard, Thierry Gonsalves, Stephen G. Hopkins, Phil M. Riazi, Sheila Saddic, Louis A. Sambuughin, Nyamkhishig Saxena, Richa Stowell, Kathryn Weber, James Rosenberg, Henry Biesecker, Leslie G. |
author_facet | Johnston, Jennifer J. Dirksen, Robert T. Girard, Thierry Gonsalves, Stephen G. Hopkins, Phil M. Riazi, Sheila Saddic, Louis A. Sambuughin, Nyamkhishig Saxena, Richa Stowell, Kathryn Weber, James Rosenberg, Henry Biesecker, Leslie G. |
author_sort | Johnston, Jennifer J. |
collection | PubMed |
description | PURPOSE: As a ClinGen Expert Panel (EP) we set out to adapt the ACMG pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly-inherited malignant hyperthermia (MH). METHODS: We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework. RESULTS: Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hot spot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cut-offs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and two as variants of uncertain significance. CONCLUSION: Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels. |
format | Online Article Text |
id | pubmed-8263483 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-82634832021-09-25 Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Classifications in Malignant Hyperthermia Susceptibility Johnston, Jennifer J. Dirksen, Robert T. Girard, Thierry Gonsalves, Stephen G. Hopkins, Phil M. Riazi, Sheila Saddic, Louis A. Sambuughin, Nyamkhishig Saxena, Richa Stowell, Kathryn Weber, James Rosenberg, Henry Biesecker, Leslie G. Genet Med Article PURPOSE: As a ClinGen Expert Panel (EP) we set out to adapt the ACMG pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly-inherited malignant hyperthermia (MH). METHODS: We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework. RESULTS: Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hot spot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cut-offs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and two as variants of uncertain significance. CONCLUSION: Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels. 2021-03-25 2021-07 /pmc/articles/PMC8263483/ /pubmed/33767344 http://dx.doi.org/10.1038/s41436-021-01125-w Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Johnston, Jennifer J. Dirksen, Robert T. Girard, Thierry Gonsalves, Stephen G. Hopkins, Phil M. Riazi, Sheila Saddic, Louis A. Sambuughin, Nyamkhishig Saxena, Richa Stowell, Kathryn Weber, James Rosenberg, Henry Biesecker, Leslie G. Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Classifications in Malignant Hyperthermia Susceptibility |
title | Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Classifications in Malignant Hyperthermia Susceptibility |
title_full | Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Classifications in Malignant Hyperthermia Susceptibility |
title_fullStr | Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Classifications in Malignant Hyperthermia Susceptibility |
title_full_unstemmed | Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Classifications in Malignant Hyperthermia Susceptibility |
title_short | Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Classifications in Malignant Hyperthermia Susceptibility |
title_sort | variant curation expert panel recommendations for ryr1 pathogenicity classifications in malignant hyperthermia susceptibility |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263483/ https://www.ncbi.nlm.nih.gov/pubmed/33767344 http://dx.doi.org/10.1038/s41436-021-01125-w |
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