Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug;11(3):120-124.
doi: 10.5582/irdr.2022.01067.

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

Yoko Inoue  1   2 , Osamu Machida  1   3 , Yosuke Kita  4 , Toshiyuki Yamamoto  1   2
Affiliations

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

Yoko Inoue et al. Intractable Rare Dis Res. 2022 Aug.

Abstract

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; diagnostic odyssey; interpretation; sequence variant.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Distribution of the interpretation of the variants for each inheritance trait represented by a 100% stacked chart. The numbers in the boxes indicate the corresponding numbers of the variants. *, Statistically significant (p < 0.05); #, no significant difference.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Wu AC, McMahon P, Lu C. Ending the diagnostic odyssey-Is whole-genome sequencing the answer? JAMA Pediatr. 2020; 174:821-822. - PMC - PubMed
    1. Umlai UI, Bangarusamy DK, Estivill X, Jithesh PV. Genome sequencing data analysis for rare disease gene discovery. Brief Bioinform. 2022; 23:bbab363. - PubMed
    1. Takahashi Y, Date H, Oi H, Adachi T, Imanishi N, Kimura E, Takizawa H, Kosugi S, Matsumoto N, Kosaki K, Matsubara Y; IRUD Consortium, Mizusawa H. Six years' accomplishment of the Initiative on Rare and Undiagnosed Diseases: nationwide project in Japan to discover causes, mechanisms, and cures. J Hum Genet. 2022. doi: 10.1038/s10038-022-01025-0. - PMC - PubMed
    1. Najafi A, Caspar SM, Meienberg J, Rohrbach M, Steinmann B, Matyas G. Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies. Clin Genet. 2020; 97:235-245. - PMC - PubMed
    1. Kim YE, Ki CS, Jang MA. Challenges and considerations in sequence variant interpretation for mendelian disorders. Ann Lab Med. 2019; 39:421-429. - PMC - PubMed