ClinVar

Description

Variant summary: NPHS2 c.851C>T (p.Ala284Val) results in a non-conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 150926 control chromosomes (gnomAD v3.1, genomes dataset). The variant, c.851C>T, has been reported in the literature in multiple homozygous individuals affected with Nephrotic Syndrome Type 2, which progressed to end-stage renal disease (e.g. Tsukaguchi_2002, Karle_2002, Kitzler_2018). This variant was also reported in compound heterozygous state in numerous patients with a well-reported, frequent, genotype-dependent risk variant p.R229Q (e.g. Tsukaguchi_2002, Machuca_2009, Santin_2011), and occasionally also with other (potentially) pathogenic variants in trans (e.g. Park_2020). These data indicate that the variant is very likely to be associated with disease. An extensive study performed by Tory_2014, demonstrated that the A284V podocin protein was mislocalized in the cytoplasmic compartment (either when coexpressed with the WT or with the R229Q podocin), in contrast, while WT podocin reached the plasma membrane, podocin R229Q was retained in the cytoplasm in cells coexpressing podocin A284V (on the other hand, both the WT podocin and podocin R229Q were localized to the plasma membrane when coexpressed together); authors concluded that these interactions mimicked a dominant-negative effect of A284V on the R229Q variant protein. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=3) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.