NM_014625.4(NPHS2):c.413G>A (p.Arg138Gln) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000414576.38

Allele description

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

Gene:

NPHS2:NPHS2 stomatin family member, podocin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q25.2

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.179561327C>T
NG_007535.1:g.19623G>A
NM_001297575.2:c.413G>A
NM_014625.4:c.413G>AMANE SELECT
NP_001284504.1:p.Arg138Gln
NP_055440.1:p.Arg138Gln
NP_055440.1:p.Arg138Gln
LRG_887t1:c.413G>A
LRG_887:g.19623G>A
LRG_887p1:p.Arg138Gln
NC_000001.10:g.179530462C>T
NM_001297575.2:c.413G>A
NM_014625.2:c.413G>A
NM_014625.3:c.413G>A
Q9NP85:p.Arg138Gln
p.ARG138GLN
p.R138Q

Protein change:

R138Q; ARG138GLN

Links:

UniProtKB: Q9NP85#VAR_010233; OMIM: 604766.0001; dbSNP: rs74315342

NCBI 1000 Genomes Browser:

rs74315342

Molecular consequence:

NM_001297575.2:c.413G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014625.4:c.413G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000331676	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 1, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000491110	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 17, 2021)	germline	clinical testing	Citation Link,
SCV000614347	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 24, 2020)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 11729243, 24089165, 14570703, 24500309, 18443213, 12649741, 14675423, 21415313, 21171529, 20947785, 29982877, 32129207, 17942957, 28780565, 10742096, 15253708, 18216321, 19371226, 19406966, 26467025
SCV000950662	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11729243, 20798252, 24856380, 25852895, 10742096, 17371932, 12649741, 14570703, 14675423, 29049388, 28492532
SCV001246105	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2020)	germline	clinical testing	Citation Link,
SCV001931502	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001953082	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001980631	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CD80, suPAR and nephrotic syndrome in a case of NPHS2 mutation.

Cara-Fuentes G, Araya C, Wei C, Rivard C, Ishimoto T, Reiser J, Johnson RJ, Garin EH.

Nefrologia. 2013;33(5):727-31. doi: 10.3265/Nefrologia.pre2013.Jun.12085.

PubMed [citation]

PMID:: 24089165

Podocyte-associated gene mutation screening in a heterogeneous cohort of patients with sporadic focal segmental glomerulosclerosis.

Laurin LP, Lu M, Mottl AK, Blyth ER, Poulton CJ, Weck KE.

Nephrol Dial Transplant. 2014 Nov;29(11):2062-9. doi: 10.1093/ndt/gft532. Epub 2014 Feb 4.

PubMed [citation]

PMID:: 24500309

See all PubMed Citations (26)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000331676.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From GeneDx, SCV000491110.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV000614347.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000950662.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001246105.23

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001931502.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001953082.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001980631.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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