ClinVar Genomic variation as it relates to human health
NM_014625.4(NPHS2):c.871C>T (p.Arg291Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014625.4(NPHS2):c.871C>T (p.Arg291Trp)
Variation ID: 5369 Accession: VCV000005369.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q25.2 1: 179552605 (GRCh38) [ NCBI UCSC ] 1: 179521740 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 12, 2024 Nov 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014625.4:c.871C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055440.1:p.Arg291Trp missense NM_144696.6:c.3032-1907G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001297575.2:c.667C>T NP_001284504.1:p.Arg223Trp missense NC_000001.11:g.179552605G>A NC_000001.10:g.179521740G>A NG_007535.1:g.28345C>T NG_033075.1:g.191886G>A LRG_887:g.28345C>T LRG_887t1:c.871C>T LRG_887p1:p.Arg291Trp Q9NP85:p.Arg291Trp - Protein change
- R291W, R223W
- Other names
- -
- Canonical SPDI
- NC_000001.11:179552604:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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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. |
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AXDND1 | - | - | - |
GRCh38 GRCh37 |
58 | 265 |
NPHS2 | - | - |
GRCh38 GRCh37 |
338 | 547 |
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. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Oct 10, 2023 | RCV000005700.17 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 21, 2023 | RCV000681927.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 6, 2023 | RCV003352747.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 1, 2023 | RCV003993738.1 |
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
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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. |
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Pathogenic
(Apr 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Idiopathic nephrotic syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360832.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: NPHS2 c.871C>T (p.Arg291Trp) results in a non-conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Five … (more)
Variant summary: NPHS2 c.871C>T (p.Arg291Trp) results in a non-conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249882 control chromosomes. c.871C>T has been reported in the literature in compound heterozygous and homozygous genotypes with another variant p.R229Q among multiple individuals affected with Steroid Resistant Nephrotic syndrome (SRNS) (Zhang_2004, Tory_2014, Buscher_2016, Sadowski_2015, Miko_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that demonstrates that p.Arg291Trp podocin mutant localizes to the late endosomes (Roselli_2004). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Steroid-resistant nephrotic syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812328.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in NPHS2 is predicted to replace arginine with tryptophan at codon 291, p.(Arg291Trp). The arginine residue is located in the Band 7 … (more)
This sequence change in NPHS2 is predicted to replace arginine with tryptophan at codon 291, p.(Arg291Trp). The arginine residue is located in the Band 7 region in the cytoplasmic domain. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (6/19,898 alleles) in the East Asian population, consistent with recessive disease. This variant has been detected in multiple individuals with steroid-resistant nephrotic syndrome, both in the homozygous state and compound heterozygous for the variant and a pathogenic variant (PMID: 15327385, 24509478, 28117080, 31027891, 33193607). The variant segregates with renal disease in multiple individuals in at least one family (PMID: 33193607). The variant demonstrates altered podocin cellular localisation and nephrin trafficking in functional assays (PMID: 15496146, 36167728). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.904). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Supporting, PM2_Supporting, PP3. (less)
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Pathogenic
(Jul 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004063240.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The c.871C>T (p.R291W) alteration is located in exon 7 (coding exon 7) of the NPHS2 gene. This alteration results from a C to T substitution … (more)
The c.871C>T (p.R291W) alteration is located in exon 7 (coding exon 7) of the NPHS2 gene. This alteration results from a C to T substitution at nucleotide position 871, causing the arginine (R) at amino acid position 291 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (6/281266) total alleles studied. The highest observed frequency was 0.03% (6/19898) of East Asian alleles. This variant has been confirmed in trans with a pathogenic variant in multiple individuals with clinical features of NPHS2-related nephrotic syndrome (Ottlewski, 2019; Karle, 2002) and was found to segregate with disease in a large affected family (Tsukaguchi, 2002). This amino acid position is highly conserved in available vertebrate species. Multiple functional studies demonstrated that the p.R291W alteration mislocalizes podocin and nephrin in vitro (Dorison, 2023; Roselli, 2004; Nishibori, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Nephrotic syndrome, type 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042713.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
The missense c.871C>Tp.Arg291Trp variant in NPHS2 gene has been reported in compound heterozygous state in multiple individuals affected with nephrotic syndrome Büscher AK, et. al.,2016; … (more)
The missense c.871C>Tp.Arg291Trp variant in NPHS2 gene has been reported in compound heterozygous state in multiple individuals affected with nephrotic syndrome Büscher AK, et. al.,2016; Mikó Á, et. al., 2018. Experimental studies have shown that this variant alters NPHS2 podocin protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin Stráner P, et. al., 2018. The p.Arg291Trp variant has been reported with allele frequency of 0.002% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Pathogenic multiple submissions. The amino acid Arg at position 291 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg291Trp in NPHS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the kidney (present)
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Likely pathogenic
(May 05, 2014)
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criteria provided, single submitter
Method: literature only
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Nephrotic syndrome, idiopathic, steroid-resistant
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220295.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Nephrotic syndrome, type 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893929.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nephrotic syndrome, type 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004049255.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Pathogenic
(Oct 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nephrotic syndrome, type 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004191530.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002123053.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 291 of the NPHS2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 291 of the NPHS2 protein (p.Arg291Trp). This variant is present in population databases (rs74315348, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of steroid-resistant nephrotic syndrome (PMID: 10742096, 11805166, 12464671, 28476686, 31308032). It has been reported in trans with the variant p.Arg229Gln in related affected individuals. This suggests that the combination of p.Arg229Gln and this variant may be clinically significant. ClinVar contains an entry for this variant (Variation ID: 5369). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has been shown to alter NPHS2 (podocin) protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin (PMID: 15327385, 18823551, 29660491). 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)
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Pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809411.1
First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018 |
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Pathogenic
(Jun 04, 2018)
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no assertion criteria provided
Method: clinical testing
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Nephrotic syndrome, type 2
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000863895.1
First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
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Pathogenic
(Apr 01, 2000)
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no assertion criteria provided
Method: literature only
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NEPHROTIC SYNDROME, TYPE 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025882.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2022 |
Comment on evidence:
In a family with autosomal recessive steroid-resistant nephrotic syndrome (600995) previously reported by Fuchshuber et al. (1995), Boute et al. (2000) identified an 871C-T transition … (more)
In a family with autosomal recessive steroid-resistant nephrotic syndrome (600995) previously reported by Fuchshuber et al. (1995), Boute et al. (2000) identified an 871C-T transition in exon 7 of the NPHS2 gene, which resulted in an arg291-to-trp (R291W) substitution. This mutation was identified on the paternal allele; a mutation on the maternal allele was not identified. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Kidney Organoids Generated Using an Allelic Series of NPHS2 Point Variants Reveal Distinct Intracellular Podocin Mistrafficking. | Dorison A | Journal of the American Society of Nephrology : JASN | 2023 | PMID: 36167728 |
Familial Focal Segmental Glomerulosclerosis With Late-Onset Presentation and R229Q/R291W Podocin Mutations. | Riguetti MTP | Frontiers in genetics | 2020 | PMID: 33193607 |
A Systematic Analysis of Major Susceptible Genes in Childhood-onset Steroid-resistant Nephrotic Syndrome. | Li Y | Annals of clinical and laboratory science | 2019 | PMID: 31308032 |
Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease. | Ottlewski I | Kidney international | 2019 | PMID: 31027891 |
The mutation-dependent pathogenicity of NPHS2 p.R229Q: A guide for clinical assessment. | Mikó Á | Human mutation | 2018 | PMID: 30260545 |
C-terminal oligomerization of podocin mediates interallelic interactions. | Stráner P | Biochimica et biophysica acta. Molecular basis of disease | 2018 | PMID: 29660491 |
Mutation spectrum of genes associated with steroid-resistant nephrotic syndrome in Chinese children. | Wang Y | Gene | 2017 | PMID: 28476686 |
Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. | Bierzynska A | Kidney international | 2017 | PMID: 28117080 |
Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid-Resistant Nephrotic Syndrome. | Büscher AK | Clinical journal of the American Society of Nephrology : CJASN | 2016 | PMID: 26668027 |
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 |
Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. | Tory K | Nature genetics | 2014 | PMID: 24509478 |
NPHS2 variation in focal and segmental glomerulosclerosis. | Tonna SJ | BMC nephrology | 2008 | PMID: 18823551 |
NPHS2 (Podocin) mutations in nephrotic syndrome. Clinical spectrum and fine mechanisms. | Caridi G | Pediatric research | 2005 | PMID: 15817495 |
Mutations in NPHS2 in sporadic steroid-resistant nephrotic syndrome in Chinese children. | Yu Z | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2005 | PMID: 15769810 |
Disease-causing missense mutations in NPHS2 gene alter normal nephrin trafficking to the plasma membrane. | Nishibori Y | Kidney international | 2004 | PMID: 15496146 |
In vivo expression of podocyte slit diaphragm-associated proteins in nephrotic patients with NPHS2 mutation. | Zhang SY | Kidney international | 2004 | PMID: 15327385 |
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 |
NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. | Tsukaguchi H | The Journal of clinical investigation | 2002 | PMID: 12464671 |
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 |
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 |
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Text-mined citations for rs74315348 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.