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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Evaluation of population frequency data for mitoch ...
Evaluation of population frequency data for mitochondrial variant interpretation
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The document discusses the challenges of reporting variants of uncertain clinical significance (VUSs) in clinical genetic testing and the use of frequency data to aid in variant classification. The current guidelines recommend using frequency thresholds of 1% or higher for pathogenic variants and 0.5% for likely benign variants in mitochondrial DNA. However, these thresholds may lead to a high number of VUSs, making it difficult for clinicians to make a diagnosis. <br /><br />The study evaluated mitochondrial variants from databases and found that 98% of pathogenic variants had frequencies below 0.03%, while all benign variants had frequencies above this threshold. Additionally, 44% of benign variants had frequencies below the expert panel threshold of 0.5%. Among the VUSs, 31% had frequencies higher than most pathogenic variants but below the expert panel threshold. The combined frequency of these VUSs was 3.3%, suggesting they are likely benign.<br /><br />Based on these findings, the authors propose a different frequency threshold for evaluating mitochondrial variants. They suggest a tiered approach using a frequency threshold of 0.01%, referred to as Disease Allele Frequency (DAF). They provide guidelines for classifying variants based on their frequency relative to the DAF, with different levels of evidence assigned accordingly. Variants with frequencies ≥1% can be classified as benign, while variants with frequencies between 0.1% and 1% can be classified as likely benign. Variants with frequencies between 0.03% and 0.1% are given a moderate level of evidence, and further investigation is needed for classification.<br /><br />In conclusion, the study highlights the need for a different frequency threshold for evaluating mitochondrial variants and proposes a new approach based on a threshold of 0.01%. This approach may help improve variant classification and reduce the number of VUSs, facilitating clinical decision-making.
Asset Subtitle
Presenting Author - Glenn A. Maston, PhD; Co-Author - Pernilla von Nandelstadh, PhD; Co-Author - Sari Tuupanen, PhD; Co-Author - Izabela Karbassi, PhD, FACMG; Co-Author - Juha W. Koskenvuo, MD, PhD;
Meta Tag
Mitochondria
Co-Author
Pernilla von Nandelstadh, PhD
Co-Author
Sari Tuupanen, PhD
Co-Author
Izabela Karbassi, PhD, FACMG
Co-Author
Juha W. Koskenvuo, MD, PhD
Presenting Author
Glenn A. Maston, PhD
Keywords
VUSs
clinical genetic testing
variant classification
pathogenic variants
benign variants
mitochondrial DNA
frequency thresholds
mitochondrial variants
expert panel threshold
Disease Allele Frequency
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