Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene. Human mutation Zastrow, D. B., Baudet, H., Shen, W., Thomas, A., Si, Y., Weaver, M. A., Lager, A. M., Liu, J., Mangels, R., Dwight, S. S., Wright, M. W., Dobrowolski, S. F., Eilbeck, K., Enns, G. M., Feigenbaum, A., Lichter-Konecki, U., Lyon, E., Pasquali, M., Watson, M., Blau, N., Steiner, R. D., Craigen, W. J., Mao, R., ClinGen Inborn Errors of Metabolism Working Group 2018; 39 (11): 1569–80


The ClinGen Inborn Errors of Metabolism Working Group was tasked with creating a comprehensive, standardized knowledge base of genes and variants for metabolic diseases. Phenylalanine hydroxylase (PAH) deficiency was chosen to pilot development of the Working Group's standards and guidelines. A PAH variant curation expert panel (VCEP) was created to facilitate this process. Following ACMG-AMP variant interpretation guidelines, we present the development of these standards in the context of PAH variant curation and interpretation. Existing ACMG-AMP rules were adjusted based on disease (6) or strength (5) or both (2). Disease adjustments include allele frequency thresholds, functional assay thresholds, and phenotype-specific guidelines. Our validation of PAH-specific variant interpretation guidelines is presented using 85 variants. The PAH VCEP interpretations were concordant with existing interpretations in ClinVar for 69 variants (81%). Development of biocurator tools and standards are also described. Using the PAH-specific ACMG-AMP guidelines, 714 PAH variants have been curated and will be submitted to ClinVar. We also discuss strategies and challenges in applying ACMG-AMP guidelines to autosomal recessive metabolic disease, and the curation of variants in these genes.

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