VCV000005360.72 - ClinVar

NM_014625.4(NPHS2):c.413G>A (p.Arg138Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(26)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014625.4(NPHS2):c.413G>A (p.Arg138Gln)

Variation ID: 5360 Accession: VCV000005360.72

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q25.2 1: 179561327 (GRCh38) [ NCBI UCSC ] 1: 179530462 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Dec 22, 2024	Mar 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014625.4:c.413G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055440.1:p.Arg138Gln	missense
NM_001297575.2:c.413G>A	NP_001284504.1:p.Arg138Gln	missense
NC_000001.11:g.179561327C>T
NC_000001.10:g.179530462C>T
NG_007535.1:g.19623G>A
LRG_887:g.19623G>A
LRG_887t1:c.413G>A	LRG_887p1:p.Arg138Gln
	Q9NP85:p.Arg138Gln

... more HGVS ... less HGVS

Protein change

R138Q

Other names

Canonical SPDI

NC_000001.11:179561326:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00054

Trans-Omics for Precision Medicine (TOPMed) 0.00059

The Genome Aggregation Database (gnomAD), exomes 0.00060

Exome Aggregation Consortium (ExAC) 0.00068

Links

ClinGen: CA117446 UniProtKB: Q9NP85#VAR_010233 OMIM: 604766.0001 dbSNP: rs74315342 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NPHS2		-	-	GRCh38 GRCh37	348	565

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Nephrotic syndrome, type 2	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Mar 30, 2024	RCV000005691.34
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Feb 9, 2024	RCV000414576.44
Nephrotic range proteinuria	Pathogenic (1)	no assertion criteria provided	-	RCV001003814.2
Chronic kidney disease	Likely pathogenic (1)	criteria provided, single submitter	May 28, 2020	RCV001171338.2
Steroid-resistant nephrotic syndrome	Pathogenic (1)	no assertion criteria provided	Sep 16, 2020	RCV001275640.2
Nephrotic syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, single submitter	Mar 6, 2018	RCV001328321.5
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 20, 2021	RCV004584317.1
NPHS2-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 31, 2024	RCV003944802.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Nephrotic syndrome, type 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001164373.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (6) PubMed: 23242530‚ 24500309‚ 11729243‚ 19406966‚ 12649741‚ 29382718 Comment: 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 … (more) 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). (less)
Likely pathogenic (May 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Chronic kidney disease (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Cavalleri Lab, Royal College of Surgeons in Ireland Accession: SCV001328285.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: PS3, PP3, PP5
Pathogenic (Nov 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Nephrotic syndrome, type 2 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194214.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020	Publications: PubMed (8) PubMed: 11805166‚ 10742096‚ 21415313‚ 21171529‚ 24089165‚ 12649741‚ 14570703‚ 14675423 Comment: 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, … (more) 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. (less)
Pathogenic (Jun 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV001752562.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 Comment: This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
Pathogenic (Nov 17, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491110.3 First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect with altered protein folding and accumulation in the endoplasmic reticulum instead of the plasma membrane as seen in … (more) Published functional studies demonstrate a damaging effect with altered protein folding and accumulation in the endoplasmic reticulum instead of the plasma membrane as seen in the wild type (Ohashi et al., 2003; Roselli et al., 2004). Furthermore, homozygous knock-in mouse models presented with nephrotic syndrome with features similar to human disease (Tabatabaeifar et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28780565, 21171529, 21415313, 19406966, 14570703, 24464702, 18443213, 24500309, 24089165, 14675423, 10742096, 25903641, 26211502, 29982877, 19495806, 29382718, 29049388, 11854170, 25852895, 24856380, 19371226, 20947785, 18216321, 15253708, 14978175, 25349199, 29474669, 31028937, 31980526, 32581362, 32585588, 12649741) (less)
Pathogenic (Jan 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 2 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018363.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000950662.5 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 11729243‚ 20798252‚ 24856380‚ 25852895‚ 10742096‚ 17371932‚ 12649741‚ 14570703‚ 14675423‚ 29049388 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 138 of the NPHS2 protein (p.Arg138Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 138 of the NPHS2 protein (p.Arg138Gln). This variant is present in population databases (rs74315342, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 11729243, 20798252, 24856380, 25852895). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 10742096, 17371932). ClinVar contains an entry for this variant (Variation ID: 5360). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPHS2 function (PMID: 12649741, 14570703, 14675423, 29049388). 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. (less)
Pathogenic (Feb 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414083.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (9) PubMed: 10742096‚ 12649741‚ 14570703‚ 14675423‚ 18443213‚ 19406966‚ 24227627‚ 29049388‚ 29382718 Comment: PP3, PM3_strong, PS3, PS4_moderate Number of individuals with the variant: 1
Pathogenic (Dec 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246105.27 First in ClinVar: May 09, 2020 Last updated: Dec 22, 2024	Number of individuals with the variant: 3
Pathogenic (Dec 08, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Idiopathic nephrotic syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699382.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 15253708‚ 14978175 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 01, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331676.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 10742096 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPHS2 Number of individuals with the variant: 2 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Nephrotic syndrome, type 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000351504.3 First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019	Publications: PubMed (8) PubMed: 11854170‚ 25349199‚ 25852895‚ 24856380‚ 24500309‚ 24227627‚ 11729243‚ 10742096 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 26, 2019)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Nephrotic syndrome, type 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal, inherited	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150184.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Observation 1: Zygosity: Compound Heterozygote Sex: male Tissue: blood Observation 2: Zygosity: Compound Heterozygote Sex: female Tissue: blood
Pathogenic (Jun 24, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000614347.3 First in ClinVar: Jan 09, 2017 Last updated: Jan 26, 2021	Publications: PubMed (19) PubMed: 11729243‚ 24089165‚ 14570703‚ 24500309‚ 18443213‚ 12649741‚ 14675423‚ 21415313‚ 21171529‚ 20947785‚ 29982877‚ 32129207‚ 17942957‚ 28780565‚ 10742096‚ 15253708‚ 18216321‚ 19371226‚ 19406966 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004191523.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Dec 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002506421.2 First in ClinVar: May 07, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PS1,PM1,PM2,PP3,PP4,PP5 Number of individuals with the variant: 1 Clinical Features: Nephrotic syndrome (present) Zygosity: Homozygote Age: 0-9 years Sex: male Tissue: blood
Pathogenic (Feb 15, 2002)	no assertion criteria provided Method: literature only	NEPHROTIC SYNDROME, TYPE 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025873.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (4) PubMed: 8589695‚ 10742096‚ 11729243‚ 11854170 Comment on evidence: In 6 families with steroid-resistant nephrotic syndrome type 2 (NPHS2; 600995), 3 of which were previously reported by Fuchshuber et al. (1995), Boute et al. … (more) In 6 families with steroid-resistant nephrotic syndrome type 2 (NPHS2; 600995), 3 of which were previously reported by Fuchshuber et al. (1995), Boute et al. (2000) identified a 413G-A transition in exon 3 of the NPHS2 gene, resulting in an arg138-to-gln (R138Q) substitution. The mutation was found in homozygosity in 4 families and in compound heterozygosity in another (see 604766.0009); in 1 family, only a paternal R138Q mutation was detected. This mutation causes the replacement of a residue that is highly conserved among stomatin-like protein family members and is probably crucial for podocin function. Caridi et al. (2001) found a homozygous R138Q mutation in 3 patients with sporadic steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis. Onset occurred before age 2 years and all progressed to renal failure necessitating transplantation. Koziell et al. (2002) identified a homozygous R138Q mutation in an English patient with a severe form of NPHS2 with congenital onset. (less)
Pathogenic (-)	no assertion criteria provided Method: research	Nephrotic range proteinuria Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001162265.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 1 Sex: male
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953082.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980631.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (Mar 06, 2018)	no assertion criteria provided Method: clinical testing	Nephrotic syndrome Affected status: yes Allele origin: unknown	Sydney Genome Diagnostics, Children's Hospital Westmead Accession: SCV001449390.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Number of individuals with the variant: 1 Zygosity: Compound Heterozygote
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Steroid-resistant nephrotic syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460930.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931502.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely pathogenic (Nov 10, 2017)	no assertion criteria provided Method: literature only	Nephrotic syndrome Affected status: yes Allele origin: germline	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002106946.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (1) PubMed: 29127259 Zygosity: Compound Heterozygote
Pathogenic (Aug 31, 2024)	no assertion criteria provided Method: clinical testing	NPHS2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004769508.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The NPHS2 c.413G>A variant is predicted to result in the amino acid substitution p.Arg138Gln. This variant has been reported in the homozygous or compound heterozygous … (more) The NPHS2 c.413G>A variant is predicted to result in the amino acid substitution p.Arg138Gln. This variant has been reported in the homozygous or compound heterozygous state in many individuals with steroid-resistant nephrotic syndrome and is the most common pathogenic variant in European individuals (commonly referred to as R138Q; Boute et al. 2000. PubMed ID: 10742096; Bouchireb et al. 2013. PubMed ID: 24227627; Malina et al. 2009. PubMed ID: 19495806; Bińczak-Kuleta et al. 2014. PubMed ID: 24856380). Functional studies indicate this variant causes aberrant accumulation in the endoplasmic reticulum instead of localization to the plasma membrane (Roselli et al. 2004. PubMed ID: 14675423). A mouse model hemizygous for this variant developed nephrotic syndrome and showed elevated mRNA expression of the mutant allele and podocin protein loss (Tabatabaeifar et al. 2017. PubMed ID: 29049388). This variant is reported in 0.11% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
Uncertain significance (Mar 18, 2016)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: reference population Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Nephrotic syndrome, type 2 Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267425.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (3) PubMed: 10742096‚ 24089165‚ 19406966 Number of individuals with the variant: 1 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean
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Comment:

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).

Comment:

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.

Comment:

Published functional studies demonstrate a damaging effect with altered protein folding and accumulation in the endoplasmic reticulum instead of the plasma membrane as seen in the wild type (Ohashi et al., 2003; Roselli et al., 2004). Furthermore, homozygous knock-in mouse models presented with nephrotic syndrome with features similar to human disease (Tabatabaeifar et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28780565, 21171529, 21415313, 19406966, 14570703, 24464702, 18443213, 24500309, 24089165, 14675423, 10742096, 25903641, 26211502, 29982877, 19495806, 29382718, 29049388, 11854170, 25852895, 24856380, 19371226, 20947785, 18216321, 15253708, 14978175, 25349199, 29474669, 31028937, 31980526, 32581362, 32585588, 12649741)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 138 of the NPHS2 protein (p.Arg138Gln). This variant is present in population databases (rs74315342, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 11729243, 20798252, 24856380, 25852895). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 10742096, 17371932). ClinVar contains an entry for this variant (Variation ID: 5360). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPHS2 function (PMID: 12649741, 14570703, 14675423, 29049388). 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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

The NPHS2 c.413G>A variant is predicted to result in the amino acid substitution p.Arg138Gln. This variant has been reported in the homozygous or compound heterozygous state in many individuals with steroid-resistant nephrotic syndrome and is the most common pathogenic variant in European individuals (commonly referred to as R138Q; Boute et al. 2000. PubMed ID: 10742096; Bouchireb et al. 2013. PubMed ID: 24227627; Malina et al. 2009. PubMed ID: 19495806; Bińczak-Kuleta et al. 2014. PubMed ID: 24856380). Functional studies indicate this variant causes aberrant accumulation in the endoplasmic reticulum instead of localization to the plasma membrane (Roselli et al. 2004. PubMed ID: 14675423). A mouse model hemizygous for this variant developed nephrotic syndrome and showed elevated mRNA expression of the mutant allele and podocin protein loss (Tabatabaeifar et al. 2017. PubMed ID: 29049388). This variant is reported in 0.11% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
NPHS2 gene mutations in azerbaijani children with steroid-resistant nephrotic syndrome.	Baylarov R	Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia	2020	PMID: 32129207
Use of genomic and functional analysis to characterize patients with steroid-resistant nephrotic syndrome.	Kitzler TM	Pediatric nephrology (Berlin, Germany)	2018	PMID: 29982877
Endoplasmic reticulum-retained podocin mutants are massively degraded by the proteasome.	Serrano-Perez MC	The Journal of biological chemistry	2018	PMID: 29382718
Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.	Warejko JK	Clinical journal of the American Society of Nephrology : CJASN	2018	PMID: 29127259
An inducible mouse model of podocin-mutation-related nephrotic syndrome.	Tabatabaeifar M	PloS one	2017	PMID: 29049388
Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: analysis and recommendations.	Sen ES	Journal of medical genetics	2017	PMID: 28780565
A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.	Sadowski CE	Journal of the American Society of Nephrology : JASN	2015	PMID: 25349199
Steroid-resistant nephrotic syndrome with mutations in NPHS2 (podocin): report from a three-generation family.	Jain V	Clinical kidney journal	2014	PMID: 25852895
Retrospective mutational analysis of NPHS1, NPHS2, WT1 and LAMB2 in children with steroid-resistant focal segmental glomerulosclerosis - a single-centre experience.	Bińczak-Kuleta A	Bosnian journal of basic medical sciences	2014	PMID: 24856380
Podocyte-associated gene mutation screening in a heterogeneous cohort of patients with sporadic focal segmental glomerulosclerosis.	Laurin LP	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2014	PMID: 24500309
NPHS2 mutations in steroid-resistant nephrotic syndrome: a mutation update and the associated phenotypic spectrum.	Bouchireb K	Human mutation	2014	PMID: 24227627
CD80, suPAR and nephrotic syndrome in a case of NPHS2 mutation.	Cara-Fuentes G	Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia	2013	PMID: 24089165
NPHS2 p.V290M mutation in late-onset steroid-resistant nephrotic syndrome.	Kerti A	Pediatric nephrology (Berlin, Germany)	2013	PMID: 23242530
Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome.	Santín S	Clinical journal of the American Society of Nephrology : CJASN	2011	PMID: 21415313
Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome.	Santín S	Clinical journal of the American Society of Nephrology : CJASN	2011	PMID: 20947785
Plasmapheresis-induced clinical improvement in a patient with steroid-resistant nephrotic syndrome due to podocin (NPHS2) gene mutation.	Skálová S	Acta medica (Hradec Kralove)	2010	PMID: 21171529
Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome.	Büscher AK	Clinical journal of the American Society of Nephrology : CJASN	2010	PMID: 20798252
Clinical features and long-term outcome of nephrotic syndrome associated with heterozygous NPHS1 and NPHS2 mutations.	Caridi G	Clinical journal of the American Society of Nephrology : CJASN	2009	PMID: 19406966
Nucleotide variations in the NPHS2 gene in Greek children with steroid-resistant nephrotic syndrome.	Megremis S	Genetic testing and molecular biomarkers	2009	PMID: 19371226
Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis.	Löwik M	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2008	PMID: 18443213
Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome.	Hinkes B	Journal of the American Society of Nephrology : JASN	2008	PMID: 18216321
NPHS2 variation in sporadic focal segmental glomerulosclerosis.	McKenzie LM	Journal of the American Society of Nephrology : JASN	2007	PMID: 17942957
Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).	Hinkes BG	Pediatrics	2007	PMID: 17371932
NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.	Weber S	Kidney international	2004	PMID: 15253708
Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome.	Ruf RG	Journal of the American Society of Nephrology : JASN	2004	PMID: 14978175
Plasma membrane targeting of podocin through the classical exocytic pathway: effect of NPHS2 mutations.	Roselli S	Traffic (Copenhagen, Denmark)	2004	PMID: 14675423
Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains.	Huber TB	Human molecular genetics	2003	PMID: 14570703
Intracellular mislocalization of mutant podocin and correction by chemical chaperones.	Ohashi T	Histochemistry and cell biology	2003	PMID: 12649741
Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration.	Koziell A	Human molecular genetics	2002	PMID: 11854170
Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome.	Karle SM	Journal of the American Society of Nephrology : JASN	2002	PMID: 11805166
Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis.	Caridi G	Journal of the American Society of Nephrology : JASN	2001	PMID: 11729243
NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.	Boute N	Nature genetics	2000	PMID: 10742096
Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis.	Fuchshuber A	Human molecular genetics	1995	PMID: 8589695
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPHS2	-	-	-	-
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Text-mined citations for rs74315342 ...

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Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_014625.4(NPHS2):c.413G>A (p.Arg138Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs74315342 ...