1-179561327-C-T

Variant names:

• chr1-179561327-C-T
• rs74315342
• NM_014625.4:c.413G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5 PP2 PP5_Very_Strong

The NM_014625.4(NPHS2):​c.413G>A​(p.Arg138Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000797 in 1,613,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (0 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 U:1
• Conservation: PhyloP100: 6.19
• Publications: 83 publications found

Genes affected

NPHS2 (HGNC:13394): (NPHS2 stomatin family member, podocin) This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

NPHS2 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-179561327-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3064145.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.68612 (below the threshold of 3.09). Trascript score misZ: 0.038296 (below the threshold of 3.09). GenCC associations: The gene is linked to nephrotic syndrome, type 2, familial idiopathic steroid-resistant nephrotic syndrome.
• PP5: Variant 1-179561327-C-T is Pathogenic according to our data. Variant chr1-179561327-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014625.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	NM_014625.4	MANE Select	c.413G>A	p.Arg138Gln	missense	Exon 3 of 8	NP_055440.1
	NPHS2	NM_001297575.2		c.413G>A	p.Arg138Gln	missense	Exon 3 of 7	NP_001284504.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS2	ENST00000367615.9	TSL:1 MANE Select	c.413G>A	p.Arg138Gln	missense	Exon 3 of 8	ENSP00000356587.4
	NPHS2	ENST00000367616.4	TSL:1	c.413G>A	p.Arg138Gln	missense	Exon 3 of 7	ENSP00000356588.4

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000597 AC: 150 AN: 251306 AF XY: 0.000685

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000826 AC: 1207 AN: 1461038 Hom.: 0 Cov.: 29 AF XY: 0.000783 AC XY: 569 AN XY: 726904

African (AFR) AF: 0.000149 AC: 5 AN: 33466

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00104 AC: 1155 AN: 1111268

Other (OTH) AF: 0.000580 AC: 35 AN: 60362

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000512 AC XY: 38 AN XY: 74264

African (AFR) AF: 0.000193 AC: 8 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000811 Hom.: 0

Bravo AF: 0.000586

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000675 AC: 82

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:11 Uncertain:1

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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).

Feb 15, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Nov 18, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

May 22, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 26, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Dec 08, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: reference population

May 22, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 1286 heterozygote(s), 0 homozygote(s)) ; This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified pathogenic by >15 clinical laboratories (ClinVar); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from arginine to glutamine; This variant is heterozygous; This gene is associated with autosomal recessive disease; Variant is located in the annotated Band 7 domain (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome, type 2 (MIM#600995); Inheritance information for this variant is not currently available in this individual.

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:10

Jun 24, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 17, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 15, 2023

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the NPHS2 gene demonstrated a sequence change, c.413G>A, in exon 3 that results in an amino acid change, p.Arg138Gln. The p.Arg138Gln change affects a highly conserved amino acid residue located in a domain of the NPHS2 protein that is known to be functional. The p.Arg138Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Experimental studies have demonstrated that this sequence change may impact function of NPHS2 (PMID: 12649741, 29382718, 14570703, 14675423, 29049388). This sequence change has previously been described in a multiple individuals with a diagnosis of nephrotic syndrome (PMID: 23242530, 11729243, 19406966, 24500309, 11729243). This sequence change has been described in the gnomAD database with a frequency of 0.11467% in the non-Finnish European subpopulation (dbSNP rs74315342). Collectively, this evidence indicates that this sequence change is pathogenic.

Feb 09, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM3_strong, PS3, PS4_moderate

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPHS2 protein function with a positive predictive value of 95%. 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.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nephrotic syndrome Pathogenic:2

Mar 06, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 10, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Nephrotic range proteinuria Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Chronic kidney disease Pathogenic:1

May 28, 2020

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3, PP3, PP5

Steroid-resistant nephrotic syndrome Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

NPHS2-related disorder Pathogenic:1

Aug 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

See cases Pathogenic:1

Dec 20, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS1,PM1,PM2,PP3,PP4,PP5

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.86
MPC		0.99
ClinPred		0.18	T
GERP RS		5.8
Varity_R		0.94
gMVP		0.95
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74315342; hg19: chr1-179530462;