loading page

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
Author Profile
Lora Bean
PerkinElmer Genomics
Author Profile
Izabela Karbassi
Quest Diagnostics
Author Profile
Katelynn Beattie
GeneDx
Author Profile
Thierry Bienvenu
Inserm
Author Profile
Hope Bonin
Central Manchester University Hospitals NHS Foundation Trust
Author Profile
Ping Fang
Baylor Genetics
Author Profile
John Christodoulou
Murdoch Childrens Research Institute
Author Profile
Michael Friez
Greenwood Genetic Center
Author Profile
Maria Helgeson
Invitae Corporation
Author Profile
Rahul Krishnaraj
Children's Hospital at Westmead
Author Profile
Linyan Meng
Baylor College of Medicine
Author Profile
Lindsey Mighion
GeneDx
Author Profile
Jeffrey Neul
Vanderbilt Kennedy Center
Author Profile
Alan Percy
UAB
Author Profile
Simon Ramsden
Manchester University NHS Foundation Trust
Author Profile
Huda Y. Zoghbi
Baylor College of Medicine
Author Profile
Soma Das
The University of Chicago
Author Profile

Abstract

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.

Peer review status:IN REVISION

16 Jul 2021Submitted to Human Mutation
20 Jul 2021Assigned to Editor
20 Jul 2021Submission Checks Completed
03 Aug 2021Reviewer(s) Assigned
23 Aug 2021Review(s) Completed, Editorial Evaluation Pending
30 Aug 2021Editorial Decision: Revise Minor