Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes

Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes—ENG and ACVRL1

Published:2024-05-18 Issue: Volume:2024 Page:1-13
ISSN:1098-1004
Container-title:Human Mutation
language:en
Short-container-title:Human Mutation

Author:

DeMille Desiree¹^ORCID,McDonald Jamie²^ORCID,Bernabeu Carmelo³^ORCID,Racher Hilary⁴⁵^ORCID,Olivieri Carla⁶^ORCID,Cantarini Claudia⁶^ORCID,Sbalchiero Anna⁶^ORCID,Thompson Bryony A.⁷^ORCID,Jovine Luca⁸^ORCID,Shovlin Claire L.⁹^ORCID,Dupuis-Girod Sophie¹⁰^ORCID,Lesca Gaetan¹⁰^ORCID,Tusseau Maud¹⁰^ORCID,Ganguly Arupa¹¹^ORCID,Kasthuri Raj S.¹²^ORCID,Jessen Jaime⁴^ORCID,Massink Maarten P. G.¹³^ORCID,Ichikawa Shoji¹⁴^ORCID,Bayrak-Toydemir Pinar²^ORCID

Affiliation:

1. Genomics Analysis, ARUP Laboratories, Salt Lake City, UT 84108, USA

2. Department of Pathology, University of Utah, Salt Lake City, UT 84108, USA

3. Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain

4. Impact Genetics/Dynacare, Brampton, L6T 5M3, Canada

5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M5S 1A8, Canada

6. Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy

7. Department of Pathology, Royal Melbourne Hospital, Melbourne 3050, Australia

8. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 141 83, Sweden

9. National Heart and Lung Institute, Imperial College, London W12 0HN, UK

10. Hospices Civils de Lyon, National HHT Reference Center and Department of Medical Genetics, Femme Mère Enfants Hospital, 69500 Bron, France

11. Department of Genetics, PSOM, University of Pennsylvania, Philadelphia, PA 19104, USA

12. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

13. Department of Genetics, University Medical Center Utrecht, Utrecht 3584CX, Netherlands

14. Ambry Genetics, Aliso Viejo, CA 92656, USA

Abstract

The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the ENG and ACVRL1 genes. Eight of the original ACMG/AMP rules were determined to not be applicable for ENG- or ACVRL1-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution.

Funder

UNC/Kaiser

Publisher

Hindawi Limited

Link

http://downloads.hindawi.com/journals/humu/2024/3043736.pdf

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