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Recommendations by the ClinGen Rett/Angelman-like Expert Panel for Gene-specific Variant Interpretation Methods
  • +15
  • Dianalee McKnight,
  • Lora Bean,
  • Izabela Karbassi,
  • Katelynn Beattie,
  • Thierry Bienvenu,
  • Hope Bonin,
  • Ping Fang,
  • John Christodoulou,
  • Michael Friez,
  • Maria Helgeson,
  • Rahul Krishnaraj,
  • Linyan Meng,
  • Lindsey Mighion,
  • Jeffrey Neul,
  • Alan Percy,
  • Simon Ramsden,
  • Huda Y. Zoghbi,
  • Soma Das
Dianalee McKnight
Invitae Corporation

Corresponding Author:[email protected]

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Lora Bean
PerkinElmer Genomics
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Izabela Karbassi
Quest Diagnostics
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Katelynn Beattie
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Thierry Bienvenu
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Hope Bonin
Central Manchester University Hospitals NHS Foundation Trust
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Ping Fang
Baylor Genetics
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John Christodoulou
Murdoch Childrens Research Institute
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Michael Friez
Greenwood Genetic Center
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Maria Helgeson
Invitae Corporation
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Rahul Krishnaraj
Children's Hospital at Westmead
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Linyan Meng
Baylor College of Medicine
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Lindsey Mighion
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Jeffrey Neul
Vanderbilt Kennedy Center
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Alan Percy
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Simon Ramsden
Manchester University NHS Foundation Trust
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Huda Y. Zoghbi
Baylor College of Medicine
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Soma Das
The University of Chicago
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The genes MECP2, CDKL5, FOXG1, UBE3A, SLC9A6, and TCF4 present unique challenges for current ACMG/AMP variant interpretation guidelines. To address those challenges, the Rett and Angelman-like Disorders Variant Curation Expert Panel (Rett/AS VCEP) drafted gene-specific modifications. A pilot study was conducted to test the clarity and accuracy of using the customized variant interpretation criteria. Multiple curators obtained the same interpretation for 78 out of the 87 variants (~90%), indicating appropriate usage of the modified guidelines the majority of times by all the curators. The classification of 13 variants changed using these criteria specifications compared to when the variants were originally curated and as present in ClinVar. Many of these changes were due to internal data shared from laboratory members however some changes were because of changes in strength of criteria. There were no two step classification changes and only 1 clinically relevant change (Likely pathogenic to VUS). The Rett/AS VCEP hopes that these gene-specific variant curation rules and the assertions provided help clinicians, clinical laboratories, and others interpret variants in these genes but also other fully penetrant, early-onset genes associated with rare disorders.
16 Jul 2021Submitted to Human Mutation
20 Jul 2021Submission Checks Completed
20 Jul 2021Assigned to Editor
03 Aug 2021Reviewer(s) Assigned
23 Aug 2021Review(s) Completed, Editorial Evaluation Pending
30 Aug 2021Editorial Decision: Revise Minor
05 Nov 20211st Revision Received
05 Nov 2021Submission Checks Completed
05 Nov 2021Assigned to Editor
08 Nov 2021Reviewer(s) Assigned
12 Nov 2021Review(s) Completed, Editorial Evaluation Pending
22 Nov 2021Editorial Decision: Accept
Aug 2022Published in Human Mutation volume 43 issue 8 on pages 1097-1113. 10.1002/humu.24302