Intractable Rare Dis Res. 2022;11(3):120-124. (DOI: 10.5582/irdr.2022.01067)

Need for revision of the ACMG/AMP guidelines for interpretation of X-linked variants

Inoue Y, Machida O, Kita Y, Yamamoto T


The guidelines provided by American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) (ACMG/AMP guidelines) suggest a framework for the classification of clinical variants. However, the interpretations can be inconsistent, with each definition sometimes proving to be ambiguous. In particular, there can be difficulty with interpretation of variants related to the X-linked recessive trait. To confirm whether there are biases in the interpretation of inherited traits, we reanalyzed variants reported prior to the release of the ACMG/AMP guidelines. As expected, the interpretation ratio as pathogenic or likely pathogenic was significantly lower for variants related to the X-linked recessive trait. Evaluation of variants related to the X-linked recessive trait, hence, need to consider whether the variant is identified only in males in accordance with the X-linked recessive trait. The ACMG/AMP guidelines should be revised to eliminate the bias revealed in this study.

KEYWORDS: ACMG/AMP guidelines, X-linked recessive, interpretation, sequence variant, diagnostic odyssey

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