The relationship between the ATG5 gene and spinocerebellar ataxia, autosomal recessive 25 (SCAR25), was evaluated using the ClinGen Clinical Validity Framework as of July 13, 2022 and re-evaluated on October 23, 2025. ATG5 encodes autophagy 5 protein, a protein involved in cellular autophagy via binding the ATG12 protein (PMID: 9759731, PMID: 9852036) to form a complex needed for formation of the autophagic isolation membrane, which helps deliver cytoplasmic components to lysosomes for degradation in macroautophagy (PMID: 11266458). The lymphoblastoid cells of patients with biallelic ATG5 variants reported showed reduced levels of the ATG5-ATG12 protein complex and decreased autophagic flux, consistent with impaired autophagy due to impeded ATG5-ATG12 interaction (PMID: 26812546).
The disease mechanism of SCAR25 is loss of function. SCAR25 was first reported in 2005 (PMID:15981765) and the first report of biallelic variants in ATG5 among patients with SCAR25 was in 2016 (PMID: 26812546). In this report, a homozygous missense variant, c.366A>T (p.E122D), was reported to segregate in a consanguineous Turkish family with two affected members; as noted above, lymphoblastoid cells of patients (who were homozygous for this ATG5 variant) showed reduced levels of the ATG5-ATG12 protein complex and decreased autophagic flux, supporting that the variant resulted in impaired autophagy due to impeded ATG5-ATG12 interaction (PMID: 26812546).To date, this first report (PMID: 26812546) appears to be the only report of biallelic ATG5 variants among patients with SCAR25.
In addition to the case-level (genetic) evidence (4 points; including 2 points for the variant and 2 points for segregation), there is also experimental evidence supporting the relationship between SCAR25 and ATG5 (6 points total). Experimental evidence for the relationship between ATG5 and SCAR25 includes the biochemical function of the gene product (autophagy 5) being consistent with the reduced autophagic flux found in individuals with SCAR25 (PMID: 26812546), the biochemical and clinical features of a ATG5 knockout Drosophila model (PMID: 26812546), and rescue of a a ATG5 knockout Drosophila model via reexpression of a wild-type ATG5 transgene (PMID: 26812546).
In summay, the relationship between ATG5 and SCAR25 is limited. While the total points awarded (10 points) would allow for the classificaiton of "moderate", only a single family with a homozygous single variant has been reported. Therefore, additional case-level evidence is needed to support a causal role. This clinical validity classification of limited was first approved by the ClinGen Lysosomal Diseases GCEP on July 21, 2022 (SOP v9), and re-evaluated by the ClinGen General IEM GCEP on October 24, 2025 (SOP v11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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