The variant found in the TBL1XR1 gene (c.1184 T > A (p.Tyr395Phe)) for the unsolved case in the TBL1XR1 case phenotypic cluster did not explain the typical Amyotrophic lateral sclerosis (ALS) phenotype of the case based on the feedback from the clinical expert, although it is described as likely pathogenic, pointing out the need for variant reclassification. This evidence concerns the gene TBL1XR1 and amyotrophic lateral sclerosis.