ClinVar Miner

Submissions for variant NM_014625.3(NPHS2):c.413G>A (p.Arg138Gln) (rs74315342)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000005691 SCV000267425 uncertain significance Idiopathic nephrotic syndrome 2016-03-18 criteria provided, single submitter reference population
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000414576 SCV000331676 pathogenic not provided 2017-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000005691 SCV000351504 pathogenic Idiopathic nephrotic syndrome 2017-04-27 criteria provided, single submitter clinical testing The NPHS2 c.413G>A (p.Arg138Gln) missense variant is a well-established European founder variant that represents approximately 30%-40% of variant alleles in individuals with steroid-resistant nephrotic syndrome (SRNS) from that population (Bouchireb et al. 2014). Across a small selection of the available literature, the p.Arg138Gln variant is reported in a total of 71 individuals including in a homozygous state in 37 affected individuals, in a compound heterozygous state in 31 affected individuals, in a heterozygous state where a second variant was not identified in two affected siblings, and in a heterozygous state in one unaffected family member (Boute et al. 2000; Caridi et al. 2001; Koziell et al. 2002; Laurin et al. 2014; Binczak-Kuleta et al. 2014; Jain et al. et al. 2014; Sadowski et al. 2015). Control data are unavailable in these studies, though the variant is reported at a frequency of 0.00118 in the European (non-Finnish) population of the Exome Aggregation Consortium. A review by Bouchireb et al. (2014) indicates that the Arg138 residue is highly conserved among stromatin-like protein family members and the p.Arg138Gln variant protein is retained in the endoplasmic reticulum, rather than targeting normally to the plasma membrane. Bouchireb et al. (2014) also report that a knock-in mouse model homozygous for the equivalent of this variant presents at birth with severe proteinuria and progresses to end-stage kidney disease by five weeks of life. Based on the collective evidence, the p.Arg138Gln variant is classified as pathogenic for steroid-resistant nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000414576 SCV000491110 pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing The R138Q pathogenic variant in the NPHS2 gene is the most common pathogenic variant among individuals with steroid-resistant nephrotic syndrome from a European background and has been seen in affected individuals who are heterozygous, compound heterozygous, or homozygous for the R138Q variant (Bouchireb et al., 2014). Functional studies show the R138Q variant affects protein folding and the affected protein accumulates in the endoplasmic reticulum instead of the plasma membrane as seen in the wild type (Ohashi et al., 2003; Roselli et al., 2004). The R138Q variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R138Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Missense variants in the same and nearby residues (R138P, L139R, L142P) have been reported in the Human Gene Mutation Database in association with nephrotic syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R138Q as a pathogenic variant.
Athena Diagnostics Inc RCV000414576 SCV000614347 pathogenic not provided 2020-06-24 criteria provided, single submitter clinical testing This variant is one of the most common variants associated with autosomal recessive steroid-resistant nephrotic syndrome (PMID 15253708), therefore the frequency of this variant in the general population is consistent with pathogenicity. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease, and data include affected and unaffected individuals from multiple families.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000005691 SCV000699382 pathogenic Idiopathic nephrotic syndrome 2016-12-08 criteria provided, single submitter clinical testing Variant summary: The NPHS2 c.413G>A (p.Arg138Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 82/121298 control chromosomes at a frequency of 0.000676, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). The variant is considered a common disease variant and has been reported as an European founder mutation. The variant is reported in numerous affected individuals in the literature in both the homozygous and compound heterozygous state. Additionally, functional studies show that while the variant resulted in a protien that retains the ability to homo-oligomerize, the protein is retained in the ER and fails to recruit nephrin to lipid drafts (Huber_2003). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000414576 SCV000950662 pathogenic not provided 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 138 of the NPHS2 protein (p.Arg138Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs74315342, ExAC 0.1%). This variant has been observed to be homozygous or in combination with another NPHS2 variant in many individuals affected with nephrotic syndrome (PMID: 11729243, 20798252, 24856380, 25852895), and is considered a common pathogenic founder mutation in European populations (PMID: 10742096, 14978175, 17371932). ClinVar contains an entry for this variant (Variation ID: 5360). Experimental studies have shown that this missense change disrupts protein function (PMID: 12649741, 14570703, 14675423, 29049388). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000005691 SCV001164373 pathogenic Idiopathic nephrotic syndrome 2018-12-03 criteria provided, single submitter research The heterozygous p.Arg138Gln variant in NPHS2 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with nephrotic syndrome. This variant has also been reported pathogenic in ClinVar (Variation ID: 5360). The p.Arg138Gln variant in NPHS2 has been reported in the homozygous and heterozygous state, in 20 individuals of European descent with nephrotic syndrome (PMID: 23242530, 24500309,11729243, 19406966), and has been identified in 0.1153% (146/126602) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs74315342). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role and its prevalence in European individuals suggests a founder effect. Functional studies with mammalian cells provide some evidence that the p.Arg138Gln variant may impact protein function by preventing localization to the plasma membrane from the endoplasmic reticulum and increasing protein degradation (PMID: 12649741, 29382718). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with 4 loss of function variants (1 in this study, 3 from the literature) and in an individual with nephrotic syndrome increases the likelihood that the p.Arg138Gln variant is pathogenic (PMID: 23242530). In summary, this variant meets criteria to be classified as pathogenic for nephrotic syndrome in an autosomal recessive manner based on evidence from functional studies with mammal cells and multiple occurrences with pathogenic variants in individuals with nephrotic syndrome. ACMG/AMP Criteria applied: PP3, PS3, PM3_Strong (Richards 2015).
Myriad Women's Health, Inc. RCV000005691 SCV001194214 pathogenic Idiopathic nephrotic syndrome 2019-11-18 criteria provided, single submitter clinical testing NM_014625.2(NPHS2):c.413G>A(R138Q) is classified as pathogenic in the context of NPHS2-related nephrotic syndrome. Sources cited for classification include the following: PMID 11805166, 10742096, 21415313, 21171529, 24089165, 12649741, 14570703 and 14675423. Classification of NM_014625.2(NPHS2):c.413G>A(R138Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000414576 SCV001246105 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland RCV001171338 SCV001328285 likely pathogenic Chronic kidney disease 2020-05-28 criteria provided, single submitter research PS3, PP3, PP5
Fulgent Genetics,Fulgent Genetics RCV000005691 SCV001752562 pathogenic Idiopathic nephrotic syndrome 2021-06-30 criteria provided, single submitter clinical testing
OMIM RCV000005691 SCV000025873 pathogenic Idiopathic nephrotic syndrome 2002-02-15 no assertion criteria provided literature only
Institute of Human Genetics, Klinikum rechts der Isar RCV000005691 SCV001150184 pathogenic Idiopathic nephrotic syndrome 2019-04-26 no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003814 SCV001162265 pathogenic Nephrotic range proteinuria no assertion criteria provided research
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001328321 SCV001449390 pathogenic Nephrotic syndrome 2018-03-06 no assertion criteria provided clinical testing
Natera, Inc. RCV001275640 SCV001460930 pathogenic Steroid-resistant nephrotic syndrome 2020-09-16 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000414576 SCV001931502 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000414576 SCV001953082 likely pathogenic not provided no assertion criteria provided clinical testing

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