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Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene
Author(s) -
Zastrow Diane B.,
Baudet Heather,
Shen Wei,
Thomas Amanda,
Si Yue,
Weaver Meredith A.,
Lager Angela M.,
Liu Jixia,
Mangels Rachel,
Dwight Selina S.,
Wright Matt W.,
Dobrowolski Steven F.,
Eilbeck Karen,
Enns Gregory M.,
Feigenbaum Annette,
LichterKonecki Uta,
Lyon Elaine,
Pasquali Marzia,
Watson Michael,
Blau Nenad,
Steiner Robert D.,
Craigen William J.,
Mao Rong
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23649
Subject(s) - phenylalanine hydroxylase , context (archaeology) , inborn error of metabolism , biology , genetics , computational biology , medical genetics , bioinformatics , gene , phenylalanine , endocrinology , paleontology , amino acid
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.