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

Dominant pathogenic variants in ATP1A3 can occur anywhere in the coding sequence and can cause a wide range of clinical presentations. A practical problem is that sequencing services use one of 3 different mRNA transcripts with different lengths to number the candidate variants. Genetic reports often identify an ATP1A3 variant as a VUS when it is actually well validated. Only 1 transcript, the MANE Select transcript that encodes a protein of 1,013 amino acids, is well supported by evidence. Misidentification of variants in ATP1A3 is disadvantageous when it prevents a confident diagnosis. We illustrate the differences among the 3 transcripts and their merits. Sequencing services should use the MANE Select transcript.