ClinVar Genomic variation as it relates to human health
NM_014625.4(NPHS2):c.851C>T (p.Ala284Val)
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.851C>T (p.Ala284Val)
Variation ID: 562398 Accession: VCV000562398.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q25.2 1: 179552625 (GRCh38) [ NCBI UCSC ] 1: 179521760 (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 Oct 1, 2018 Feb 14, 2024 Dec 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014625.4:c.851C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055440.1:p.Ala284Val missense NM_144696.6:c.3032-1887G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001297575.2:c.647C>T NP_001284504.1:p.Ala216Val missense NC_000001.11:g.179552625G>A NC_000001.10:g.179521760G>A NG_007535.1:g.28325C>T NG_033075.1:g.191906G>A LRG_887:g.28325C>T LRG_887t1:c.851C>T LRG_887p1:p.Ala284Val - Protein change
- A284V, A216V
- Other names
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- Canonical SPDI
- NC_000001.11:179552624: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00008
- Links
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
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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 |
39 | 246 |
NPHS2 | - | - |
GRCh38 GRCh37 |
332 | 541 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Dec 9, 2023 | RCV000681863.8 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 22, 2023 | RCV000781678.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 10, 2022 | RCV002223136.1 |
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
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. |
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Pathogenic
(Jun 30, 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: SCV001752756.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
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Pathogenic
(Mar 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV000842935.3
First in ClinVar: Oct 01, 2018 Last updated: Sep 19, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. 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. The variant is located in a region that is considered important for protein function and/or structure. (less)
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Pathogenic
(Mar 10, 2022)
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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: SCV000919906.2
First in ClinVar: Jun 03, 2019 Last updated: Apr 23, 2022 |
Comment:
Variant summary: NPHS2 c.851C>T (p.Ala284Val) 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.851C>T (p.Ala284Val) 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 4e-05 in 150926 control chromosomes (gnomAD v3.1, genomes dataset). The variant, c.851C>T, has been reported in the literature in multiple homozygous individuals affected with Nephrotic Syndrome Type 2, which progressed to end-stage renal disease (e.g. Tsukaguchi_2002, Karle_2002, Kitzler_2018). This variant was also reported in compound heterozygous state in numerous patients with a well-reported, frequent, genotype-dependent risk variant p.R229Q (e.g. Tsukaguchi_2002, Machuca_2009, Santin_2011), and occasionally also with other (potentially) pathogenic variants in trans (e.g. Park_2020). These data indicate that the variant is very likely to be associated with disease. An extensive study performed by Tory_2014, demonstrated that the A284V podocin protein was mislocalized in the cytoplasmic compartment (either when coexpressed with the WT or with the R229Q podocin), in contrast, while WT podocin reached the plasma membrane, podocin R229Q was retained in the cytoplasm in cells coexpressing podocin A284V (on the other hand, both the WT podocin and podocin R229Q were localized to the plasma membrane when coexpressed together); authors concluded that these interactions mimicked a dominant-negative effect of A284V on the R229Q variant protein. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=3) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002817741.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); 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: 24509478, 21415313, 26211502, 16354237, 16898497, 26420286, 29982877, 32604935, 11805166, 23515051, 19876656, 19145239, 18823551, 15253708, 23349334, 21355056, 14978175, 12464671) (less)
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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: SCV004049259.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Pathogenic
(Sep 22, 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: SCV004191535.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 09, 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: SCV001231507.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the NPHS2 protein (p.Ala284Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the NPHS2 protein (p.Ala284Val). This variant is present in population databases (rs780761368, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of steroid-resistant nephrotic syndrome (PMID: 11805166, 16354237, 18823551, 23349334, 23515051, 29982877). 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: 562398). 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%. This variant has been shown to alter NPHS2 (podocin) protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin (PMID: 24509478). 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: SCV000809342.1
First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018 |
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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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Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis. | Park E | Journal of clinical medicine | 2020 | PMID: 32604935 |
Use of genomic and functional analysis to characterize patients with steroid-resistant nephrotic syndrome. | Kitzler TM | Pediatric nephrology (Berlin, Germany) | 2018 | PMID: 29982877 |
NPHS2 mutations account for only 15% of nephrotic syndrome cases. | Guaragna MS | BMC medical genetics | 2015 | PMID: 26420286 |
The amino acid mutations of the podocin in proteinuria: a meta-analysis. | Lu L | Renal failure | 2015 | PMID: 26211502 |
Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. | Tory K | Nature genetics | 2014 | PMID: 24509478 |
NPHS2 mutations in steroid-resistant nephrotic syndrome: a mutation update and the associated phenotypic spectrum. | Bouchireb K | Human mutation | 2014 | PMID: 24227627 |
Genetic screening in adolescents with steroid-resistant nephrotic syndrome. | Lipska BS | Kidney international | 2013 | PMID: 23515051 |
Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. | McCarthy HJ | Clinical journal of the American Society of Nephrology : CJASN | 2013 | PMID: 23349334 |
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 |
Screening for NPHS2 mutations may help predict FSGS recurrence after transplantation. | Jungraithmayr TC | Journal of the American Society of Nephrology : JASN | 2011 | PMID: 21355056 |
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 |
Adequate use of allele frequencies in Hispanics--a problem elucidated in nephrotic syndrome. | Chernin G | Pediatric nephrology (Berlin, Germany) | 2010 | PMID: 19876656 |
Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant. | Machuca E | Kidney international | 2009 | PMID: 19145239 |
NPHS2 variation in focal and segmental glomerulosclerosis. | Tonna SJ | BMC nephrology | 2008 | PMID: 18823551 |
Late onset of familial nephrotic syndrome associated with a compound heterozygous mutation of the podocin-encoding gene. | Ardiles LG | Nephrology (Carlton, Vic.) | 2005 | PMID: 16354237 |
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 |
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 |
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 |
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Text-mined citations for rs780761368 ...
HelpRecord last updated Mar 30, 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.