Submission Details

The relationship between the ATG7 gene and spinocerebellar ataxia, autosomal recessive 31 (SCAR31), was evaluated using the ClinGen Clinical Validity Framework as of July 18, 2022. ATG7 encodes autophagy-related 7 protein, a ubiquitin-activating enzyme E1 involved in cellular autophagy (i.e., cellular degradation and recycling of organelles and proteins) via binding ATG12 (ubiquitin-like molecule) to form a complex that mediates membrane fusion in autophagy (PMID: 11096062). ATG7 is deficient among patients with SCAR31, as reflected by severely diminished levels of ATG7 protein (measured via immunoblot analysis) in muscle cells and fibroblasts among patients with SCAR31 (PMID: 34161705), and SCAR31 patients show impaired autophagy, as reflected by accumulation of the autophagic substrate p62 and reduced autophagic flux (as reflected by reduced levels of the autophagosomal marker LC3-II) in patient fibroblasts (PMID: 34161705).

The disease mechanism of SCAR31 is loss of function. SCAR31 was first reported in 2021 (PMID: 34161705) and this was also the first report of biallelic variants in ATG7 among patients with SCAR31 (PMID: 34161705). In this report, a total of nine different ATG7 variants were noted among 12 individuals from five families and the variants segregated with disease in all families. The variants reported included nonsense, splice-site, and missense variants, and for eight of the nine variants, direct functional assessments demonstrated that they impaired wild-type protein function. To date, this first report (PMID: 34161705) appears to be the only report of biallelic ATG7 variants among patients with SCAR31.

In addition to the case-level (genetic) evidence (6.1 points total), there is also experimental evidence supporting the relationship between SCAR31 and ATG7 (6 points total). Experimental evidence for the relationship between ATG5 and SCAR31 includes the biochemical function of the gene product (autophagy-related 7 protein) being consistent with the impaired autophagy found in individuals with SCAR31 (PMID: 34161705), the biochemical and clinical features of a ATG7 knockout mouse model (PMID:16625205), and rescue autophagic activity in (ATG7-deficient) patient fibroblasts via reintroduction of wild-type ATG7 (PMID: 34161705).

In sum, based on the strength of the evidence from the published report to date, the association between ATG7 and SCAR31 reaches the score range for Definitive. However, to our knowledge, only a single report of human cases exists (PMID: 34161705); thus, per the ClinGen Gene Curation, the ATG7-SCAR31 association can currently be classified as Strong, and can be classified as Definitive once there are additional follow-up publications to demonstrate that the association has been replicated over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 2, 2022 (SOP v9).