rs74315342

chr1-179561327-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 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:24 U:1
• Conservation: PhyloP100: 6.19

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 129 pathogenic changes around while only 3 benign (98%) in NM_014625.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-179561327-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3064145.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 1-179561327-C-T is Pathogenic according to our data. Variant chr1-179561327-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179561327-C-T is described in Lovd as [Pathogenic]. Variant chr1-179561327-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS2	NM_014625.4	c.413G>A	p.Arg138Gln	missense_variant	3/8	ENST00000367615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS2	ENST00000367615.9	c.413G>A	p.Arg138Gln	missense_variant	3/8	1	NM_014625.4	P1
NPHS2	ENST00000367616.4	c.413G>A	p.Arg138Gln	missense_variant	3/7	1

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

GnomAD3 exomes AF: 0.000597 AC: 150 AN: 251306 Hom.: 0 AF XY: 0.000685 AC XY: 93 AN XY: 135826

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.000580

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

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000783 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:24 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:9 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 08, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Apr 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 18, 2019	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. -
Uncertain significance, flagged submission	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	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). -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 24, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2021	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) -

Nephrotic syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Dec 20, 2021	ACMG categories: PS1,PM1,PM2,PP3,PP4,PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Mar 06, 2018	- -
Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Nov 10, 2017	- -

Nephrotic range proteinuria Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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NPHS2-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2023

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. -

Chronic kidney disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Cavalleri Lab, Royal College of Surgeons in Ireland

May 28, 2020

PS3, PP3, PP5 -

Steroid-resistant nephrotic syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

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Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;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

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs74315342; hg19: chr1-179530462;