Submission Details

TUBA4A was first reported in relation to autosomal dominant amyotrophic lateral sclerosis 22 (ALS) in 2014 (Smith BN, et al., 2014, PMID: 25374358). TUBA4A encodes an α-tubulin subunit, which together with β-tubulin constitutes the tubulin heterodimer, the building block of microtubules. ALS-associated TUBA4A variants are suggested to dysregulate neuronal function by disruption of microtubule dynamics and stability. ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 14 variants have been reported in relation to ALS (mostly missense, as well as one nonsense, one splice site, and one frameshift). Variants in this gene have been reported in at least 14 probands in 4 publications (PMIDs: 25374358, 25893256, 28069311, and 295405137). Experimentally, this gene-disease relationship is supported by its role as a constituent of cytoskeleton (PMID: 25374358), expression in the nervous system (PMID: 25374358, PMID: 30030593), and a zebrafish model with overlapping phenotypes though mechanism may differ from that proposed in patients (PMID: 38463699). TUBA4A mutants appear to disrupt microtubule dynamics and stability through a dominant-negative mechanism, however there is an absence of functional data from primary tissue of TUBA4A mutation carriers. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

This classification was previously approved by the ClinGen ALS GCEP on 09/14/2021, it was recurated on 03/27/2025 and a new zebrafish model (PMID: 38463699) was identified but there was no change of classification.