1. Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.
- Author
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Goldstein JL, McGlaughon J, Kanavy D, Goomber S, Pan Y, Deml B, Donti T, Kearns L, Seifert BA, Schachter M, Son RG, Thaxton C, Udani R, Bali D, Baudet H, Caggana M, Hung C, Kyriakopoulou L, Rosenblum L, Steiner R, Pinto E Vairo F, Wang Y, Watson M, Fernandez R, Weaver M, Clarke L, and Rehder C
- Subjects
- Infant, Newborn, Humans, United States, Genetic Testing methods, Genome, Human, Genomics methods, Genetic Variation, Glycogen Storage Disease Type II diagnosis, Glycogen Storage Disease Type II genetics
- Abstract
Accurate determination of the clinical significance of genetic variants is critical to the integration of genomics in medicine. To facilitate this process, the NIH-funded Clinical Genome Resource (ClinGen) has assembled Variant Curation Expert Panels (VCEPs), groups of experts and biocurators which provide gene- and disease- specifications to the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines. With the goal of classifying the clinical significance of GAA variants in Pompe disease (Glycogen storage disease, type II), the ClinGen Lysosomal Diseases (LD) VCEP has specified the ACMG/AMP criteria for GAA. Variant classification can play an important role in confirming the diagnosis of Pompe disease as well as in the identification of carriers. Furthermore, since the inclusion of Pompe disease on the Recommended Uniform Screening Panel (RUSP) for newborns in the USA in 2015, the addition of molecular genetic testing has become an important component in the interpretation of newborn screening results, particularly for asymptomatic individuals. To date, the LD VCEP has submitted classifications and supporting data on 243 GAA variants to public databases, specifically ClinVar and the ClinGen Evidence Repository. Here, we describe the ACMG/AMP criteria specification process for GAA, an update of the GAA-specific variant classification guidelines, and comparison of the ClinGen LD VCEP's GAA variant classifications with variant classifications submitted to ClinVar. The LD VCEP has added to the publicly available knowledge on the pathogenicity of variants in GAA by increasing the number of expert-curated GAA variants present in ClinVar, and aids in resolving conflicting classifications and variants of uncertain clinical significance., Competing Interests: Declaration of Competing Interest The following authors work or have worked in a fee-for-service diagnostic laboratory that offers GAA sequence analysis or enzymatic testing for Pompe disease: JM, DK, SG, YP, BD, TD, RU, DB, CH, LR, RS, FV, YW, and CR. RS is a medical consultant for the Wisconsin Newborn Screening Program; consults and has equity interest in Acer Therapeutics, and PTC Therapeutics; consults for DNARx, Best Doctors/Teladoc, Leadiant, Travere; has received honoraria from Medscape/WebMD, and research support from Alexion., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
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