ClinVar Miner

Submissions for variant NM_014625.3(NPHS2):c.686G>A (p.Arg229Gln) (rs61747728)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157404 SCV000207143 uncertain significance Proteinuria 2015-11-11 criteria provided, single submitter clinical testing
Counsyl RCV000576535 SCV000677983 likely pathogenic Idiopathic nephrotic syndrome 2016-07-27 criteria provided, single submitter clinical testing The pathogenicity of R229Q is dependent on the variant observed on the other chromosome. In homozygous state, R229Q is not disease-causing.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855599 SCV000699384 uncertain significance not specified 2021-04-30 criteria provided, single submitter clinical testing Variant summary: NPHS2 c.686G>A (p.Arg229Gln) results in a conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.031 in 253464 control chromosomes in the gnomAD database and publications, including 170 homozygotes. The observed variant frequency is approximately 17-fold the estimated maximal expected allele frequency for a pathogenic variant in NPHS2 causing Nephrotic Syndrome, Type 2 phenotype (0.0018), suggesting that the variant is benign. However, c.686G>A has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 2 or End-Stage Renal Disease, but also in unaffected individuals (examples- Zhang_2004, Hinkes_2007, Machuca_2009, Kerti_2013, McCarthy_2013, Benetti_2014, Guaragna_2015, Ottlewski_2019, Baylarov_2020). The Arg229Gln substitution has been extensively studied and was observed in multiple affected individuals as homozygous and compound heterozygous genotypes. Co-occurrences in patients harboring homozygous or compound heterozygous disease causing variants in the NPHS1 gene (example, Hinkes_2007), in a patient harboring a de-novo truncating variant in the PAX2 gene (example, Kerti_2013), a homozygous splice variant in the PRPRO gene (example, Ozaltin_2011) have been reported. Lastly, the variant has also been observed in a homozygous state in unaffected individuals (example, Kerti_2013, Machuca_2009). The variant is known to be associated with reduced penetrance, along with variable expressivity. An extensive study performed by Tory_2014, concluded that the pathogenicity of R229Q is highly dependent on the NPHS2 variant observed in trans. The c.686G>A in trans with certain variants located in exons 7 and 8 affecting residues Ala284, Ala288, Arg291, Ala297, Glu310, Leu327 or Gln328 have a deleterious effect due to altered heterodimerization and mislocalization of the encoded p.Arg229Gln podocin mimicking a dominant-negative effect. However, variants located in exons 1-6 in trans with R299Q are less likely to be deleterious. Multiple publications have classified the variant as a "non-neutral polymorphism." Association studies have provided conflicting results with association to risk, however, the majority of these associations did not specifically look at genotype (i.e. compound heterozygous with trans variant in exons 1-6 vs. exons 7-8) to assess risk. Miko et al. (2018) concluded in their review that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; 1. it affects residues 270-351 and alters but does not disrupt oligomerization, 2. its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:10 million). They also report that over 15% of p.R229Q associations identified so far in patients are benign. At least one publication reports experimental evidence evaluating an impact on protein function was ascertained in the context of this evaluation. The most pronounced variant effect results in 30%-50% of normal activity in ability of mutant NPHS2 (p.Arg299Gln mutant Podocin) to bind to Nephrin (NPHS1)(Tsukaguchi_2002). Eight other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=4), likely pathogenic (n=1), risk factor (n=1) and uncertain significance (n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as a genotype/variant-dependent VUS-possibly pathogenic risk factor whose final impact is influenced in a trans-associated variant specific manner.
Gharavi Laboratory,Columbia University RCV000590501 SCV000809410 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Athena Diagnostics Inc RCV000590501 SCV000842933 pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000576535 SCV001258326 uncertain significance Idiopathic nephrotic syndrome 2017-04-27 criteria provided, single submitter clinical testing 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Biology Laboratory, Fundació Puigvert RCV000576535 SCV001425126 pathogenic Idiopathic nephrotic syndrome 2020-02-01 criteria provided, single submitter research
Precision Medicine Center,Zhengzhou University RCV000576535 SCV001593093 uncertain significance Idiopathic nephrotic syndrome criteria provided, single submitter research PM1:Located in well-established functional domain PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product
Invitae RCV000590501 SCV001720310 benign not provided 2020-12-05 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000576535 SCV001737192 uncertain significance Idiopathic nephrotic syndrome 2021-05-18 criteria provided, single submitter clinical testing
OMIM RCV000005701 SCV000025883 risk factor Nephrotic syndrome, type 2, susceptibility to 2014-03-01 no assertion criteria provided literature only
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001328158 SCV001449387 risk factor Nephrotic syndrome 2018-10-19 no assertion criteria provided clinical testing This individual is heterozygous for a known variant, c.686G>A p.(Arg229Gln), in the NPHS2 gene. The c.686G>A p.(Arg229Gln) variant is reported to be associated with adult-onset steroid-resistant nephrotic syndrome and the development of FSGS when in conjunction with a second pathogenic allele (Tsukaguchi et al 2002 J Clin Invest110: 1659-1666 & Machuca et al 2009 Kidney Int 75: 727-735). It is common amongst Western European populations with an allelic frequency of 3.6% and has variable penetrance. In vitro studies show the NPHS2 p.Arg229Gln variant decreases nephrin binding to podocin and it is considered to play a role in the pathogenesis of SRNS when it is in trans with another pathogenic variant (Machuca et al 2009 Kidney Int 75:727-735). The c.686G>A variant is considered to be a risk factor allele, conferring susceptibility to nephrotic syndrome type 2.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000590501 SCV001548849 uncertain significance not provided no assertion criteria provided clinical testing The NPHS2 p.Arg229Gln variant has been reported in multiple cases of steroid-resistant nephrotic syndrome (SRNS) (McCarthy_2013_PMID:23349334; Karle_2002_PMID:11805166; Ali_2017_PMID:28529802), however this variant is also found in control databases in 8538 of 282294 chromosomes (186 homozygous) at a frequency of 0.030245 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 1715 of 25074 chromosomes (freq: 0.0684), Ashkenazi Jewish in 535 of 10354 chromosomes (freq: 0.05167), European (non-Finnish) in 4639 of 128830 chromosomes (freq: 0.03601), Other in 223 of 7196 chromosomes (freq: 0.03099), South Asian in 825 of 30590 chromosomes (freq: 0.02697), Latino in 458 of 35342 chromosomes (freq: 0.01296), African in 141 of 24966 chromosomes (freq: 0.005648), and East Asian in 2 of 19942 chromosomes (freq: 0.0001). The variant was also identified in dbSNP (ID: rs61747728), LOVD 3.0 (classified as a VUS and likely pathogenic) and ClinVar (classified as pathogenic by Athena Diagnostics and the Gharavi Laboratory at Columbia University, as likely pathogenic by Counsyl and as a VUS by Blueprint Genetics and Integrated Genetics). The p.Arg229 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. A meta-analysis of the role of the p.R229Q variant in disease found significantly higher rates of SRNS in individuals homozygous for the variant compared to individuals homozygous for the reference allele (Lu_2014_PMID:24715228). However, no association between the p.R229Q variant was found in relation to late-onset focal segmental glomerulosclerosis (FSGS) or childhood-onset nephrotic syndrome in case-control studies (Hashemi_2015_PMID:25599733; McKenzie_2007_PMID:17942957). Kerti et al. (2013) identified a 37-year-old proband with proteinuria, FSGS and end-stage renal disease who was homozygous for the p.R229Q variant and also carried a truncating variant in the PAX2 gene. The proband's unaffected father and brother were also homozygous for the p.R229Q variant suggesting that it is a modifer of disease and not causal (Kerti_2013_PMID:23800802). A comprehensive study also suggests the p.R229Q variant is only pathogenic when found in trans with known pathogenic NPHS2 3' (C-terminal) variants, such as p.A284V, p.A288T, p.R291W, p.A297V or p.E310K. Functional studies of the p.R229Q variant with these variants demonstrated abnormal localization (Tory_2014_PMID:24509478). This suggests that the pathogenicity of the p.R229Q variant is dependent on which variant it is found in trans with. In summary, this variant is classified as a variant of uncertain significance.

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