APOL1

Inheritance Pattern: AR

Disease ID:MONDO:0012931

Submitter: ClinGen

The *APOL1* gene is located on chromosome 22 at 22q12.3 and encodes the APOL1 protein. APOL1 is found associated with HDL particles in human circulation, and is capable of forming cation-conducting pores (PMID: 25730870). It acts as a trypanolytic factor, inducing lysosomal swelling and ultimate trypanosome death via its actions as a channel (PMID: 12621437, 16020735). APOL1 may have other innate immune functions, and is highly upregulated in endothelial cells and podocytes in response to interferons and TLR agonists (PMID: 25100047). Two variants in *APOL1* were first reported to dramatically increase susceptibility to focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy (HIVAN), and hypertensive end-stage kidney disease (ESKD) in 2010 (Genovese et al., PMID: 20647424). These variants, generally termed G1 (ClinVar Variation ID: 6080; encoding S342G and I384M amino-acid changes) and G2 (ClinVar Variation ID: 6081; encoding deletion of amino acids N388 and Y389), are present at high frequencies in populations with recent African ancestry (PMID: 25168832). These variants evade inhibition by the serum resistance-associated protein (SRA) expressed by Trypanosoma brucei rhodesiense to neutralize wild-type APOL1, potentially explaining the high frequency of these otherwise deleterious variants in certain African populations (PMID: 20647424). Multiple case-control and population studies have confirmed the original studies demonstrating an increased odds ratio of various (but not all) kidney and glomerular diseases in persons carrying two of the risk alleles, i.e. G1/G1, G2/G2 and compound heterozygous G1/G2 (PMID: 25100047, 25788523, 21997394, 23766536). More evidence is available in the literature (PMID: 24504811, 23520206, 24731740, 32561682, 33576823, 34352311, 34670811), but the maximum score for genetic evidence (12 pts.) has been reached. *APOL1* variants have not been associated with an increased risk of developing diabetic kidney disease (PMID: 21997396) or IgA nephropathy (21997396). Risk conferred by these variants is best described via an autosomal recessive model, though a small disease risk is conferred by the presence of one vs. no risk alleles. This is supported by a mouse model (PMID: 34350953). However, mechanistically, the G1 and G2 variants appear to act as gain-of-function, increasing APOL1 channel activity (PMID: 33380423, 32427098) and APOL1-mediated cytotoxicity (PMID: 26091559, 26699492, 32427098, 24899058, 26089538). APOL1 expression has been demonstrated in podocytes and glomeruli (PMID: 25012173, 21997392, 25100047). In a mouse model, overexpression of risk-variant, but not wild-type, APOL1 in podocytes is sufficient to induce glomerular disease mimicking many aspects of FSGS (PMID: 28218918). Homozygous risk allele, but not wild-type, APOL1 BAC mice develop progressive glomerular injury and renal failure in response to INFgamma exposure, mimicking human disease (PMID: 34350953). Additional model system evidence is available in the literature (PMID: 27864430, 27864431, 30998685, 31217349, 32854642, 33517446), but the maximum score for experimental evidence was reached. In summary, the presence of two copies of the *APOL1* risk variants G1 and/or G2 (ClinVar Variation IDs: 6080 and 6081) is definitively associated with an increased susceptibility to multiple glomerular and hypertensive kidney diseases, most prominently FSGS and HIVAN (OMIM:612551). The preferred disease name suggested for this grouping of disorders is ‘Glomerulopathy, susceptibility - *APOL1*’. This gene-disease relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AR

Disease ID:MONDO:0012931

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012931

Submitter: PanelApp Australia