Submissions for variant NM_014625.4(NPHS2):c.503G>A (p.Arg168His)

gnomAD frequency: 0.00001  dbSNP: rs530318579

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169033	SCV000220183	likely pathogenic	Nephrotic syndrome, type 2	2014-03-25	criteria provided, single submitter	literature only
Athena Diagnostics	RCV000517983	SCV000614350	pathogenic	not provided	2017-05-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517983	SCV001382268	pathogenic	not provided	2023-04-30	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 15042551, 15059485, 26467726, 28385484). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NPHS2 function (PMID: 14675423). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPHS2 protein function. ClinVar contains an entry for this variant (Variation ID: 188730). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the NPHS2 protein (p.Arg168His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169033	SCV001426848	pathogenic	Nephrotic syndrome, type 2	2020-07-12	criteria provided, single submitter	clinical testing	Variant summary: NPHS2 c.503G>A (p.Arg168His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 221108 control chromosomes. c.503G>A has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 2 (examples- Weber_2004, Ruf_2004, Mann_2019). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, indicating that the variant results in mislocalization of the protein to the endoplasmic reticulum (examples- Roselli_2004, Fan_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000169033	SCV001548499	pathogenic	Nephrotic syndrome, type 2	2021-03-30	criteria provided, single submitter	clinical testing	NPHS2 c.503G>A has been identified in the compound heterozygote or homozygous state in multiple individuals with steroid-resistant nephrotic syndrome. This NPHS2 variant (rs530318579) is rare (<0.1%) in a large population dataset (gnomAD: 3/221108 total alleles; 0.0014%; no homozygotes). There is an entry for this variant in ClinVar (Variation ID: 188730). Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across most species assessed. There is functional evidence that this variant causes mislocalization of the NPHS2 protein. We consider NPHS2 c.503G>A to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169033	SCV002813232	pathogenic	Nephrotic syndrome, type 2	2024-03-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000169033	SCV003824177	pathogenic	Nephrotic syndrome, type 2	2022-09-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169033	SCV004049279	likely pathogenic	Nephrotic syndrome, type 2	2023-04-11	criteria provided, single submitter	clinical testing
Vasylyeva lab, Texas Tech University Health Sciences Center	RCV003407626	SCV004123144	pathogenic	Finnish congenital nephrotic syndrome		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169033	SCV004191577	pathogenic	Nephrotic syndrome, type 2	2023-12-01	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000169033	SCV005051894	pathogenic	Nephrotic syndrome, type 2	2024-02-01	criteria provided, single submitter	curation
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328093	SCV001449385	pathogenic	Nephrotic syndrome	2018-09-06	no assertion criteria provided	clinical testing	This patient is an apparent homozygote for a known pathogenic variant, c.503G>A (p.Arg168His), in exon 4 of the NPHS2 gene. This variant has been previously reported in the homozygote state, and also in compound heterozygote with another pathogenic NPHS2 variant, in patients with steroid resistant nephrotic syndrome (SRNS) (Weber et al 2004 Kid Int 66:571-79). In vitro study of the NPHS2 p.Arg168His mutant in cultured podocytes showed the mutant proteins were retained in the endoplasmic reticulum (ER). This caused the mislocalisation of other critical slit diaphragm molecules, and significantly upregulated the ER stress markers, resulting in podocyte apoptosis and the cause of SRNS (Fan et al 2009 Genes Cells 14:1079-90).
Natera, Inc.	RCV001273618	SCV001456818	pathogenic	Steroid-resistant nephrotic syndrome	2020-09-16	no assertion criteria provided	clinical testing