What question did this study set out to answer?

This analysis addresses the implications of variants of uncertain significance (VUS) in genetic testing and their impact on diagnosis and management.

April 16, 2026Annals of Movement Disorders0 citationsOpen Access

Exploring Variants of Uncertain Significance in Genetic Testing and Disease Management

The enigma of VUS

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Why the study?

Genetic testing frequently yields variants of uncertain significance due to limited evidence and nuances in ACMG criteria, leaving clinicians and families uncertain.

Design

Editorial and case review

Authors

VHVikram V. Holla

Discussion

Member takes

Overview

Avoid basing clinical decisions on COL6A3/ANO3 VUS; reinforces strict ACMG application in movement disorder genetics.

Key Points

This analysis addresses the implications of variants of uncertain significance (VUS) in genetic testing and their impact on diagnosis and management.
Review of ACMG guidelines for variant classification
Analysis of case reports involving COL6A3 and ANO3 variants
Exome sequencing to identify novel variants
Two novel VUS were identified in genes associated with dystonia and paroxysmal dyskinesia.
ACMG guidelines limitations highlighted, including variable interpretation and insufficient evidence for classification.
Inconsistent segregation of variants in families raises questions about their pathogenicity.

Structured PICO

Population

Patients with movement disorders (dystonia, parkinsonism) undergoing genetic testing

Highlights the challenges of interpreting variants of uncertain significance (VUS) in movement disorders using ACMG guidelines and cautions against basing major clinical decisions solely on VUS findings.

Limitations

ACMG criteria were designed mainly for Mendelian inheritance, making application to diseases with incomplete penetrance or imprinting challenging
Variable interpretation of guidelines
Disease- and gene-specific nuances are sometimes overlooked

Cite This Study

Vikram V. Holla (2026) studied this question.

synapsesocial.com/papers/69e07c1e2f7e8953b7cbd7d4 https://doi.org/10.4103/aomd.aomd_68_25

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April 16, 2026Annals of Movement Disorders0 citationsOpen Access

Exploring Variants of Uncertain Significance in Genetic Testing and Disease Management

The enigma of VUS

View Full Paper

Ask AI

Bookmark

Why the study?

Genetic testing frequently yields variants of uncertain significance due to limited evidence and nuances in ACMG criteria, leaving clinicians and families uncertain.

Design

Editorial and case review

Authors

VHVikram V. Holla

Discussion

Member takes

Overview

Avoid basing clinical decisions on COL6A3/ANO3 VUS; reinforces strict ACMG application in movement disorder genetics.

Key Points

This analysis addresses the implications of variants of uncertain significance (VUS) in genetic testing and their impact on diagnosis and management.
Review of ACMG guidelines for variant classification
Analysis of case reports involving COL6A3 and ANO3 variants
Exome sequencing to identify novel variants
Two novel VUS were identified in genes associated with dystonia and paroxysmal dyskinesia.
ACMG guidelines limitations highlighted, including variable interpretation and insufficient evidence for classification.
Inconsistent segregation of variants in families raises questions about their pathogenicity.

Structured PICO

Population

Patients with movement disorders (dystonia, parkinsonism) undergoing genetic testing

Limitations

ACMG criteria were designed mainly for Mendelian inheritance, making application to diseases with incomplete penetrance or imprinting challenging
Variable interpretation of guidelines
Disease- and gene-specific nuances are sometimes overlooked

Cite This Study

Vikram V. Holla (2026) studied this question.

synapsesocial.com/papers/69e07c1e2f7e8953b7cbd7d4 https://doi.org/10.4103/aomd.aomd_68_25

View Full Paper

Ask AI

Bookmark