The mutation-dependent pathogenicity of NPHS2 p.R229Q: A guide for clinical assessment

Ágnes Mikó, Dóra K. Menyhárd, Ambrus Kaposi, Corinne Antignac, Kálmán Tory

Research output: Contribution to journalArticle

5 Citations (Scopus)


NPHS2, encoding podocin, is the major gene implicated in steroid-resistant nephrotic syndrome. Its c.686G>A, p.R229Q variant is the first human variant with a mutation-dependent pathogenicity; it is only pathogenic when trans-associated to specific mutations. Secondary to its high allele frequency in the European, South Asian, African, and Latino populations, its benign trans-associations can be accidentally identified in affected patients. Distinguishing pathogenic and benign p.R229Q associations can be challenging. In this paper, we present the currently known pathogenic and benign associations, and show that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; it affects the 270–351 residues and alters but does not disrupt the oligomerization, its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:106). We show that >15% of the p.R229Q associations identified so far in patients are benign.

Original languageEnglish
Pages (from-to)1854-1860
Number of pages7
JournalHuman mutation
Issue number12
Publication statusPublished - Dec 2018


  • NPHS2
  • dominant
  • interallelic interactions
  • negative
  • nephrotic syndrome
  • podocin
  • population genetics

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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