Submissions for variant NM_014625.4(NPHS2):c.871C>T (p.Arg291Trp)

gnomAD frequency: 0.00001  dbSNP: rs74315348

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000005700	SCV000220295	likely pathogenic	Nephrotic syndrome, type 2	2014-05-05	criteria provided, single submitter	literature only
Fulgent Genetics, Fulgent Genetics	RCV000005700	SCV000893929	pathogenic	Nephrotic syndrome, type 2	2021-11-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005700	SCV001360832	pathogenic	Nephrotic syndrome, type 2	2019-04-22	criteria provided, single submitter	clinical testing	Variant summary: NPHS2 c.871C>T (p.Arg291Trp) results in a non-conservative amino acid change located in the Band 7 domain (IPR001107) of 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 2e-05 in 249882 control chromosomes. c.871C>T has been reported in the literature in compound heterozygous and homozygous genotypes with another variant p.R229Q among multiple individuals affected with Steroid Resistant Nephrotic syndrome (SRNS) (Zhang_2004, Tory_2014, Buscher_2016, Sadowski_2015, Miko_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that demonstrates that p.Arg291Trp podocin mutant localizes to the late endosomes (Roselli_2004). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681927	SCV002123053	pathogenic	not provided	2024-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 291 of the NPHS2 protein (p.Arg291Trp). This variant is present in population databases (rs74315348, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of steroid-resistant nephrotic syndrome (PMID: 10742096, 11805166, 12464671, 28476686, 31308032). It has been reported in trans with the variant p.Arg229Gln in related affected individuals. This suggests that the combination of p.Arg229Gln and this variant may be clinically significant. ClinVar contains an entry for this variant (Variation ID: 5369). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has been shown to alter NPHS2 (podocin) protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin (PMID: 15327385, 18823551, 29660491). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000005700	SCV004049255	likely pathogenic	Nephrotic syndrome, type 2	2023-04-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003352747	SCV004063240	pathogenic	Inborn genetic diseases	2023-07-06	criteria provided, single submitter	clinical testing	The c.871C>T (p.R291W) alteration is located in exon 7 (coding exon 7) of the NPHS2 gene. This alteration results from a C to T substitution at nucleotide position 871, causing the arginine (R) at amino acid position 291 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (6/281266) total alleles studied. The highest observed frequency was 0.03% (6/19898) of East Asian alleles. This variant has been confirmed in trans with a pathogenic variant in multiple individuals with clinical features of NPHS2-related nephrotic syndrome (Ottlewski, 2019; Karle, 2002) and was found to segregate with disease in a large affected family (Tsukaguchi, 2002). This amino acid position is highly conserved in available vertebrate species. Multiple functional studies demonstrated that the p.R291W alteration mislocalizes podocin and nephrin in vitro (Dorison, 2023; Roselli, 2004; Nishibori, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000005700	SCV004191530	pathogenic	Nephrotic syndrome, type 2	2024-02-05	criteria provided, single submitter	clinical testing
Precision Medicine Center, Zhengzhou University	RCV000005700	SCV004218444	likely pathogenic	Nephrotic syndrome, type 2	2024-09-01	criteria provided, single submitter	clinical testing	PM2_supporting,PM3,PS3
Molecular Genetics, Royal Melbourne Hospital	RCV003993738	SCV004812328	pathogenic	Steroid-resistant nephrotic syndrome	2023-08-01	criteria provided, single submitter	clinical testing	This sequence change in NPHS2 is predicted to replace arginine with tryptophan at codon 291, p.(Arg291Trp). The arginine residue is located in the Band 7 region in the cytoplasmic domain. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (6/19,898 alleles) in the East Asian population, consistent with recessive disease. This variant has been detected in multiple individuals with steroid-resistant nephrotic syndrome, both in the homozygous state and compound heterozygous for the variant and a pathogenic variant (PMID: 15327385, 24509478, 28117080, 31027891, 33193607). The variant segregates with renal disease in multiple individuals in at least one family (PMID: 33193607). The variant demonstrates altered podocin cellular localisation and nephrin trafficking in functional assays (PMID: 15496146, 36167728). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.904). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Supporting, PM2_Supporting, PP3.
Neuberg Centre For Genomic Medicine, NCGM	RCV000005700	SCV005042713	pathogenic	Nephrotic syndrome, type 2		criteria provided, single submitter	clinical testing	The missense c.871C>Tp.Arg291Trp variant in NPHS2 gene has been reported in compound heterozygous state in multiple individuals affected with nephrotic syndrome Büscher AK, et. al.,2016; Mikó Á, et. al., 2018. Experimental studies have shown that this variant alters NPHS2 podocin protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin Stráner P, et. al., 2018. The p.Arg291Trp variant has been reported with allele frequency of 0.002% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Pathogenic multiple submissions. The amino acid Arg at position 291 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg291Trp in NPHS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000005700	SCV005090989	pathogenic	Nephrotic syndrome, type 2	2024-04-15	criteria provided, single submitter	clinical testing	PS4, PM2, PM3, PP3, PP5- The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 5369). Low frequency in gnomAD population databases. It has been previously reported as causative for steroid-resistant nephrotic syndrome (PMID: 11805166, 31308032)
OMIM	RCV000005700	SCV000025882	pathogenic	Nephrotic syndrome, type 2	2000-04-01	no assertion criteria provided	literature only
Gharavi Laboratory, Columbia University	RCV000681927	SCV000809411	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000005700	SCV000863895	pathogenic	Nephrotic syndrome, type 2	2018-06-04	no assertion criteria provided	clinical testing