ClinVar Miner

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

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Total submissions: 3
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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.

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