ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Variant summary: NPHS1 c.2746G>T (p.Ala916Ser) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251432 control chromosomes, predominantly at a frequency of 0.0034 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.0019 vs 0.0034), allowing no conclusion about variant significance. c.2746G>T has been reported in the literature in settings of multigene panel testing of individuals with a variety of renal manifestations such as FSGS, minimal change nephrotic syndrome (example, Busher_2016, Gast_2016, Lehadenkari_2004). These report(s) do not provide unequivocal conclusions about association of the variant with Nephrotic Syndrome, Type 1. At-least one co-occurrence with another pathogenic variant(s) as an alternative molecular basis of disease has been reported (Gilbert_2017, mitochondrial DNA, m.3243A>G), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

NPHS1: BS2

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).