Submission Details

ATP6AP1 was first reported in relation to ATP6AP1-CDG (also known as Immunodeficiency 47, MIM#300972) in 2016 (Jansen EJ, et al., 2016, PMID: 27231034). ATP6AP1 codes for an accessory subunit of a V‐ATPase, which normally pumps cytosolic protons into the lumen of endocytic and secretory organelles and thus maintains the acidic pH to ensure their correct function.

Hemizygous males typically present with hepatic dysfunction (ranging from increased transaminases to cholestasis, liver cirrhosis, and end stage liver failure), and immunodeficiency (frequent infections, leukopenia and low immunoglobulin levels). Hematological and neurological features are also common. Patients exhibit abnormal N-glycosylation and often abnormal 0-glycosylation patterns. Other features reported include sensorineural hearing loss, renal dysfunction, pancreatic insufficiency, and lipid and amino acid profile abnormalities, low serum copper and ceruloplasmin.

Eleven missense and one nonsense variant have been reported in 19 male probands, and 12 additional male family members, from 10 publications, were curated (Jansen et al, 2016, PMID: 27231034; Witters et al, 2018, PMID: 29192153; Dimitrov et al, 2018, PMID: 29396028; Tvina et al, 2020; PMID: 32058063, Ondruskova et al, 2020, PMID: 32216104; Yang et al, 2021, PMID: 34621841; Barua et al, 2022, PMID: 35732497; Alharbi et al, 2023, PMID: 35732497; Dang et al, 2023, PMID: 36719165; Semenova et al, 2023; PMID: 37108612). The mechanism of pathogenicity appears to be loss of function. All genotyped patients were hemizygous males; where the inheritance pattern is known 6 probands had a de novo variant and 13 had a maternally inherited variant. The ATP6AP1:c.1036G>A (p.Glu346Lys) variant is a recurrent de novo variant, and is inherited in some cases (Jansen et al, 2016, PMID: 27231034; Yang et al, 2021, PMID: 34621841; Alharbi et al, 2023, PMID: 35732497; Dang et al, 2023, PMID: 36719165).

This gene-disease association is supported by experimental evidence showing that the function of ATP6AP1 is consistent with disease phenotypes, and that ATP6AP1 interacts with other proteins associated with CDG (Supek et al, 1994, PMID: 7929063; Wang et al, 2020, PMID: 33065002; Huttlin et al, 2017, PMID: 28514442). Specifically, ATP6AP1 (also known as Ac45) has been shown to act as a central hub for bringing the subunits of v-ATPase together for assembly into the complex (PMID: 33065002). Other genes encoding subunits of v-ATPase have been associated with CDG and are known to impact assembly or structure of the complex (Van Damme). A knock-out and conditional knock-out mouse model result in embryonic lethality (Schoonderwoert et al, 2002 PMID: 11989824; Qin et al, 2011, PMID: 22087256). In summary, there is definitive evidence to support the relationship between ATP6AP1 and ATP6AP1-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen CDG GCEP on the meeting date May 15, 2024 (SOP v10).