ClinVar Genomic variation as it relates to human health
NM_014625.4(NPHS2):c.779T>A (p.Val260Glu)
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.
Pathogenic(7); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014625.4(NPHS2):c.779T>A (p.Val260Glu)
Variation ID: 447882 Accession: VCV000447882.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q25.2 1: 179554491 (GRCh38) [ NCBI UCSC ] 1: 179523626 (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 Dec 19, 2017 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014625.4:c.779T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055440.1:p.Val260Glu missense NM_144696.6:c.3032-21A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001297575.2:c.575T>A NP_001284504.1:p.Val192Glu missense NC_000001.11:g.179554491A>T NC_000001.10:g.179523626A>T NG_007535.1:g.26459T>A NG_033075.1:g.193772A>T LRG_887:g.26459T>A LRG_887t1:c.779T>A LRG_887p1:p.Val260Glu - Protein change
- V260E, V192E
- Other names
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- Canonical SPDI
- NC_000001.11:179554490:A:T
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD) 0.00011
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 |
57 | 264 |
NPHS2 | - | - |
GRCh38 GRCh37 |
336 | 545 |
Conditions - Germline
Condition
Help
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
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000517167.5 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Jan 11, 2024 | RCV000761450.16 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001273612.1 |
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
(Dec 13, 2016)
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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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Athena Diagnostics Inc
Accession: SCV000614352.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Feb 10, 2017)
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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: SCV000699385.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The NPHS2 c.779T>A (p.Val260Glu) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and hydrophobic … (more)
Variant summary: The NPHS2 c.779T>A (p.Val260Glu) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and hydrophobic Valine (V) with a medium size and polar Glutamine (Q) located in the Band 7 domain of the protein(InterPro). 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 2/121340 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). It was reported in several nephrotic syndrome patients in homozygosity indicating causality. Moreover, in at least one family, the variant co-segregated with the disease in multiple family members further supporting a pathogenic outcome. A functional study demonstrated the variant to impair localization of NPHS2 to the plasma member ant to result accumulation of the variant in ER accumulation. Taken together, this variant is classified as pathogenic. (less)
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Uncertain significance
(Dec 30, 2017)
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criteria provided, single submitter
Method: curation
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Nephrotic syndrome, type 2
Affected status: yes
Allele origin:
unknown
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Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891536.1
First in ClinVar: Mar 24, 2019 Last updated: Mar 24, 2019 |
Geographic origin: Middle East
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Pathogenic
(Jul 31, 2019)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001451468.1
First in ClinVar: Dec 23, 2020 Last updated: Dec 23, 2020 |
Comment:
The NPHS2 c.779T>A (p.Val260Glu) variant is a missense variant that has been reported in at least four studies, in which it is found in at … (more)
The NPHS2 c.779T>A (p.Val260Glu) variant is a missense variant that has been reported in at least four studies, in which it is found in at least 23 individuals with steroid-resistant nephrotic syndrome, 20 of whom were unrelated. The variant was found in a homozygous state in at least 19 individuals and in a compound heterozygous state with a frameshift variant in another individual (Machuca et al. 2010; Kari et al. 2013; Guaragna et al. 2015; Asharam et al. 2018). The p.Val260Glu variant was found in a heterozygous state in one of 72 controls and is reported at a frequency of 0.000321 in the African population of the Genome Aggregation Database (Asharam et al. 2018). Functional analysis of the p.Val260Glu variant protein in HEK293 cells demonstrated the variant results in retention of podocin in the endoplasmic reticulum in contrast to localization of the wild type protein at the plasma membrane demonstrating a trafficking defect (Roselli et al. 2004). Based on the presence of the variant in affected individuals, functional evidence supporting gene impact, low allele frequency in public frequency databases, and in silico prediction data, the p.Val260Glu variant is classified as pathogenic for steroid-resistant nephrotic syndrome. (less)
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Nephrotic syndrome, type 2
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318789.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000447882, PMID:15253708). … (more)
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000447882, PMID:15253708). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 28658201) and was co-segregated with Nephrotic syndrome, type 2, in multiple affected family members (PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.949>=0.6, 3CNET: 0.988>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000317). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Chronic kidney disease (present) , Stage 5 chronic kidney disease (present) , Hypertensive disorder (present) , Edema (present) , Renal insufficiency (present)
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Pathogenic
(Jul 27, 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: SCV004191551.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Nephrotic syndrome, type 2
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018365.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2024)
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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: SCV001213285.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 260 of the NPHS2 protein … (more)
This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 260 of the NPHS2 protein (p.Val260Glu). This variant is present in population databases (rs775006954, gnomAD 0.03%). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 15253708, 28658201). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447882). 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: 14675423). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 17, 2018)
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no assertion criteria provided
Method: clinical testing
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Nephrotic syndrome, type 2
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132443.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Steroid-resistant nephrotic syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001456812.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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NPHS2 V260E Is a Frequent Cause of Steroid-Resistant Nephrotic Syndrome in Black South African Children. | Asharam K | Kidney international reports | 2018 | PMID: 30450462 |
Targeted Next-Generation Sequencing in Brazilian Children With Nephrotic Syndrome Submitted to Renal Transplant. | Feltran LS | Transplantation | 2017 | PMID: 28658201 |
Repository of mutations from Oman: The entry point to a national mutation database. | Rajab A | F1000Research | 2015 | PMID: 26594346 |
NPHS2 mutations account for only 15% of nephrotic syndrome cases. | Guaragna MS | BMC medical genetics | 2015 | PMID: 26420286 |
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 |
Steroid-resistant nephrotic syndrome: impact of genetic testing. | Kari JA | Annals of Saudi medicine | 2013 | PMID: 24413855 |
A molecular genetic analysis of childhood nephrotic syndrome in a cohort of Saudi Arabian families. | Al-Hamed MH | Journal of human genetics | 2013 | PMID: 23595123 |
A spectrum of novel NPHS1 and NPHS2 gene mutations in pediatric nephrotic syndrome patients from Pakistan. | Abid A | Gene | 2012 | PMID: 22565185 |
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 |
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 |
Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. | Machuca E | Journal of the American Society of Nephrology : JASN | 2010 | PMID: 20507940 |
NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. | Weber S | Kidney international | 2004 | PMID: 15253708 |
Plasma membrane targeting of podocin through the classical exocytic pathway: effect of NPHS2 mutations. | Roselli S | Traffic (Copenhagen, Denmark) | 2004 | PMID: 14675423 |
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Text-mined citations for rs775006954 ...
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.