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\begin{document}

\title{Recommendations by the ClinGen Rett/Angelman-like Expert Panel for
Gene-specific Variant Interpretation Methods}



\author[1]{Dianalee McKnight}%
\author[2]{Lora Bean}%
\author[3]{Izabela Karbassi}%
\author[4]{Katelynn Beattie}%
\author[5]{Thierry Bienvenu}%
\author[6]{Hope Bonin}%
\author[7]{Ping Fang}%
\author[8]{John Christodoulou}%
\author[9]{Michael Friez}%
\author[1]{Maria Helgeson}%
\author[10]{Rahul Krishnaraj}%
\author[11]{Linyan Meng}%
\author[4]{Lindsey Mighion}%
\author[12]{Jeffrey Neul}%
\author[13]{Alan Percy}%
\author[14]{Simon Ramsden}%
\author[11]{Huda Y. Zoghbi}%
\author[15]{Soma Das}%
\affil[1]{Invitae Corporation}%
\affil[2]{PerkinElmer Genomics}%
\affil[3]{Quest Diagnostics}%
\affil[4]{GeneDx}%
\affil[5]{Inserm}%
\affil[6]{Central Manchester University Hospitals NHS Foundation Trust}%
\affil[7]{Baylor Genetics}%
\affil[8]{Murdoch Childrens Research Institute}%
\affil[9]{Greenwood Genetic Center}%
\affil[10]{Children's Hospital at Westmead}%
\affil[11]{Baylor College of Medicine}%
\affil[12]{Vanderbilt Kennedy Center}%
\affil[13]{UAB}%
\affil[14]{Manchester University NHS Foundation Trust}%
\affil[15]{The University of Chicago}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\begin{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 (\textasciitilde{}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.%
\end{abstract}%



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\textbf{Hosted file}

\verb`RettAngelman_for Hum Mut_V3.doc`  available at \url{https://authorea.com/users/428860/articles/532666-recommendations-by-the-clingen-rett-angelman-like-expert-panel-for-gene-specific-variant-interpretation-methods}

\textbf{Hosted file}

\verb`Tables 1, 3, 4_ Rett_Angelman genes.doc`  available at \url{https://authorea.com/users/428860/articles/532666-recommendations-by-the-clingen-rett-angelman-like-expert-panel-for-gene-specific-variant-interpretation-methods}

\textbf{Hosted file}

\verb`Table 2_ ACMG_Specifications_Rett_AS_v11.doc`  available at \url{https://authorea.com/users/428860/articles/532666-recommendations-by-the-clingen-rett-angelman-like-expert-panel-for-gene-specific-variant-interpretation-methods}\selectlanguage{english}
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