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

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

Author information

1
Palo Alto Medical Foundation, Palo Alto, California.
2
Stanford University, Stanford, California.
3
University of North Carolina, Chapel Hill, North Carolina.
4
ARUP Laboratories, Salt Lake City, Utah.
5
University of Utah, Salt Lake City, Utah.
6
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York.
7
GeneDx, Gaithersburg, Maryland.
8
American College of Medical Genetics and Genomics, Bethesda, Maryland.
9
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
10
Marshfield Clinic Research Institute, Marshfield, Wisconsin.
11
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
12
Rady Children's Hospital and University of California, San Diego, California.
13
Children's Hospital of Pittsburg of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania.
14
Dietmar-Hopp Metabolic Center, University Children's Hospital, Department of General Pediatrics, Heidelberg, Germany.
15
University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
16
Baylor College of Medicine, Houston, Texas.

Abstract

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

PMID:
30311390
DOI:
10.1002/humu.23649

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