ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.2928G>T (p.Arg976Ser) (rs138656762)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169078 SCV000220249 likely pathogenic Finnish congenital nephrotic syndrome 2014-04-16 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169078 SCV000698505 pathogenic Finnish congenital nephrotic syndrome 2017-08-10 criteria provided, single submitter clinical testing Variant summary: The NPHS1 c.2928G>T (p.Arg976Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a missense change in the fibronectin type III and immunoglobulin-like domains (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant is the first nucleotide at the intron 21-exon 22 junction and 5/5 splice prediction tools predict a significant impact on normal splicing. These predictions are supported by a functional study, where exon 22 was found to be constitutively skipped in the presence of the variant via mini-gene assay. However, this in vitro result was not confirmed in vivo due to lack of patient samples (Philippe_JASN_2008). The same study showed that trafficking of nephrin (encoded by NPHS1) to the cell membrane was not altered by the variant. In the literature, numerous patients with end-stage renal failure (ESRF), minimal-change glomerulonephritis (MCNS), and focal segmental glomerulosclerosis (FSGS) have been found to carry the variant, mostly in compound heterozygosity. One patient homozygous for the variant has mild steroid resistant nephrotic syndrome (SRNS) with late onset at 37 years old (Lovric_CJASN_2014). This variant was found in the large control database ExAC and in control cohorts from the literature at a frequency of 0.0000657 (8/121742 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). One clinical diagnostic laboratory and one reputable database have classified this variant as likely pathogenic or pathogenic. Taken together, this variant is classified as pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000169078 SCV000915826 pathogenic Finnish congenital nephrotic syndrome 2018-10-08 criteria provided, single submitter clinical testing The NPHS1 c.2928G>T (p.Arg976Ser) variant has been reported across three studies in a total of ten probands in a compound heterozygous state with a diagnosis of steroid resistant nephrogenic syndrome or congenital nephrotic syndrome (Philippe et al. 2008; Santin et al. 2009; Schoeb et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.0002in the European population of the 1000 Genomes Project. In vitro exon trapping experiments are suggestive of the p.Arg976Ser variant causing altered splicing that excludes exon 22 from the NPHS1 transcript (Philippe et al. 2008). Based on the evidence, the p.Arg976Ser variant is classified as pathogenic for congenital nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV001195706 SCV001366110 pathogenic Focal segmental glomerulosclerosis 2018-09-28 criteria provided, single submitter clinical testing
Invitae RCV001222912 SCV001395035 pathogenic not provided 2019-07-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 976 of the NPHS1 protein (p.Arg976Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs138656762, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another NPHS1 variant in individuals affected with nephrotic syndrome, and has been shown to segregate with steroid-resistant nephrotic syndrome in a family (PMID: 18614772, 20172850, 24742477, 29474669). ClinVar contains an entry for this variant (Variation ID: 188761). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.