ClinVar

Description

Variant summary: NPHS1 c.791C>G (p.Pro264Arg) results in a non-conservative amino acid change located in the Immunoglobulin-like domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.015 in 275302 control chromosomes in the gnomAD database, including 54 homozygotes. The observed variant frequency is approximately 4.5 fold above the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 phenotype (0.0034), strongly suggesting that the variant is benign. c.791C>G has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1, without strong evidence for causality. In addition, the variant was found in a patient in cis with a likely pathogenic NPHS1 mutation, which was inherited from a healthy father, further supporting a benign role (Fylaktou_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.