Submission Details

AVIL – Nephrotic Syndrome Type 21 – Autosomal Recessive

The AVIL gene is located on chromosome 12 at 12q14.1 and encodes the protein Advillin, a member of the gelsolin/villin family of actin-regulatory proteins. A mutation in AVIL was first reported in association with autosomal recessive nephrotic syndrome type 21 in 2017 (Rao et al., PMID: 29058690). Nephrotic syndrome type 21 (congenital nephrotic syndrome) is characterized by significant proteinuria during the first months or years of life, leading to generalized edema. AVIL-related nephrotic syndrome type 21 (OMIM: 618594) is currently the only disease association reported for this gene.

This curation includes four variants (frameshift and missense) identified in three probands, all described in a single publication (Rao et al., PMID: 29058690). No additional evidence is available in the literature. (Genetic evidence: 3.1 points) The proposed mechanism of pathogenicity is loss of function.

This gene-disease association is supported by expression studies and in vitro functional assays (PMID: 29058690). AVIL expression was demonstrated in extracts from cultured human podocytes (PMID: 29058690). Co-localization of AVIL and PLCE1 was observed in human podocytes transfected with GFP (green fluorescent protein)-tagged, full-length (FL) mouse Avil. The interaction between AVIL and PLCE1 was further confirmed in HEK293 cells. Functional studies showed that human podocytes transfected with three patient variants (Arg135Gln, Leu425Met, or Phe656Valfs7) exhibited reduced migration rates and impaired actin-binding and -bundling abilities. Additionally, EGF stimulation increased diacylglycerol (DAG) levels in control cells treated with scrambled siRNA. Knockdown of AVIL via siRNA decreased active DAG levels. This effect was rescued by overexpression of wild-type Avil, but not by any of the three patient-derived mutant clones (Arg135Gln, Leu425Met, and Phe656Valfs7). A CRISPR-based AVIL knockdown model was also generated in zebrafish; however, the model did not exhibit a larval edema phenotype (Experimental Evidence: 2 points).

Total Score: Genetic Evidence (3.1) + Experimental Evidence (2.0) = 5.1 points

The AVIL-associated nephrotic syndrome type 21 is currently classified as ‘Limited’. This classification reflects the fact that the association has not yet been repeatedly demonstrated in both research and clinical diagnostic settings over time. This gene-disease relationship was initially evaluated by the ClinGen Glomerulopathy GCEP on June 27, 2023 (SOP Version 9), and re-evaluated on August 27, 2024 (SOP Version 10). The classification remained unchanged following the reevaluation.