Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene

Hum Mutat. 2018 Nov;39(11):1569-1580. doi: 10.1002/humu.23649.


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.

Keywords: ClinGen; PAH deficiency; inborn errors of metabolism; phenylalanine hydroxylase; variant interpretation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Databases, Genetic
  • Gene Frequency / genetics
  • Genetic Testing
  • Genetic Variation / genetics
  • Genome, Human / genetics*
  • Humans
  • Metabolism, Inborn Errors / genetics*
  • Phenylalanine Hydroxylase / genetics*


  • Phenylalanine Hydroxylase