Pathogenic Variants in ATP1A3: Why Is There So Much Confusion?

Area of Science:

• Genetics
• Molecular Biology
• Clinical Diagnostics

Background:

• Pathogenic variants in ATP1A3 cause diverse clinical presentations.
• Current sequencing services utilize multiple mRNA transcripts for variant identification, leading to inconsistencies.
• This ambiguity can result in misclassification of known pathogenic ATP1A3 variants as Variants of Uncertain Significance (VUS).

Purpose of the Study:

• To highlight the discrepancies in variant numbering caused by different ATP1A3 mRNA transcripts.
• To advocate for the adoption of a single, evidence-based transcript for accurate variant reporting.
• To improve diagnostic confidence in ATP1A3-related genetic disorders.

Main Methods:

• Comparative analysis of three different ATP1A3 mRNA transcripts.
• Evaluation of transcript evidence supporting variant identification.
• Illustration of variant misidentification due to transcript differences.

Main Results:

• Significant differences exist in variant numbering across the three commonly used ATP1A3 mRNA transcripts.
• The MANE Select transcript (1,013 amino acids) is the most robust and evidence-supported.
• Misidentification of ATP1A3 variants can lead to diagnostic uncertainty and delays.

Conclusions:

• Standardizing on the MANE Select transcript for ATP1A3 variant analysis is essential.
• Adoption of this standard will improve the accuracy and reliability of genetic reports.
• This standardization will facilitate confident diagnoses for ATP1A3-related conditions.