ClinVar Genomic variation as it relates to human health
NM_014625.4(NPHS2):c.467dup (p.Leu156fs)
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(8); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014625.4(NPHS2):c.467dup (p.Leu156fs)
Variation ID: 556941 Accession: VCV000556941.22
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 1q25.2 1: 179559745-179559746 (GRCh38) [ NCBI UCSC ] 1: 179528880-179528881 (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 Aug 5, 2018 Feb 14, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014625.4:c.467dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055440.1:p.Leu156fs frameshift NM_001297575.2:c.467dup NP_001284504.1:p.Leu156fs frameshift NM_014625.2:c.467dup NM_014625.3:c.467dupT NC_000001.11:g.179559753dup NC_000001.10:g.179528888dup NG_007535.1:g.21204dup LRG_887:g.21204dup LRG_887t1:c.467dup LRG_887p1:p.Leu156fs - Protein change
- L156fs
- Other names
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- Canonical SPDI
- NC_000001.11:179559745:AAAAAAAA:AAAAAAAAA
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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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0.00060 (AAAAAAAAA)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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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NPHS2 | - | - |
GRCh38 GRCh37 |
332 | 541 |
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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Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Oct 2, 2023 | RCV000673011.20 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 9, 2024 | RCV001069505.8 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001273619.1 |
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
(Feb 27, 2018)
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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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Counsyl
Accession: SCV000798175.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Aug 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Nephrotic syndrome, idiopathic, steroid-resistant
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000845598.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Iran
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Pathogenic
(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: SCV000891537.1
First in ClinVar: Mar 22, 2019 Last updated: Mar 22, 2019 |
Geographic origin: Middle East
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Pathogenic
(Sep 11, 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: SCV000919902.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The NPHS2 c.467dupT (p.Leu156PhefsX11) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS2 protein due to nonsense … (more)
Variant summary: The NPHS2 c.467dupT (p.Leu156PhefsX11) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 42/199282 control chromosomes at a frequency of 0.0002108, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS2 variant (0.0017678). This variant has been reported in multiple patients with steroid-resistant nephrotic syndrome and classified as pathogenic by a reputable database. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(May 08, 2019)
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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,
paternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150183.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Observation 1:
Sex: male
Tissue: blood
Observation 2:
Sex: male
Tissue: blood
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Pathogenic
(May 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: SCV002521001.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Frameshift: predicted to result in a loss … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with NPHS2 related disorder (ClinVar ID: VCV000556941 / PMID: 11729243). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Steroid-resistant nephrotic syndrome (present) , Hypertensive disorder (present) , Microscopic hematuria (present)
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Uncertain significance
(Jun 26, 2020)
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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: SCV001988396.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28780565, 28204945, 19674119, 25903641, 15338398, 11729243, 15059485, 30295827, 31209189, 33428103) (less)
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Pathogenic
(Oct 02, 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: SCV004191532.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 07, 2020)
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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: SCV002018362.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 09, 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: SCV001234675.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu156Phefs*11) in the NPHS2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu156Phefs*11) in the NPHS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS2 are known to be pathogenic (PMID: 10742096, 14701729, 15253708, 23595123). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with steroid-resistant nephrotic syndrome or focal segmental glomerulosclerosis (PMID: 11729243, 19674119, 25903641, 28204945). ClinVar contains an entry for this variant (Variation ID: 556941). For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV001456819.1
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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Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome. | Wang F | Pediatric nephrology (Berlin, Germany) | 2017 | PMID: 28204945 |
Response to cyclosporine in steroid-resistant nephrotic syndrome: discontinuation is possible. | Klaassen I | Pediatric nephrology (Berlin, Germany) | 2015 | PMID: 25903641 |
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 novel mutation in NPHS2 gene identified in a Chinese pedigree with autosomal recessive steroid-resistant nephrotic syndrome. | Sun H | Pathology | 2009 | PMID: 20001346 |
R168H and V165X mutant podocin might induce different degrees of podocyte injury via different molecular mechanisms. | Fan Q | Genes to cells : devoted to molecular & cellular mechanisms | 2009 | PMID: 19674119 |
Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome. | Hinkes B | Journal of the American Society of Nephrology : JASN | 2008 | PMID: 18216321 |
In vivo expression of podocyte slit diaphragm-associated proteins in nephrotic patients with NPHS2 mutation. | Zhang SY | Kidney international | 2004 | PMID: 15327385 |
A novel mutation of NPHS2 identified in a Chinese family. | Yu Z | Pediatric nephrology (Berlin, Germany) | 2004 | PMID: 15322893 |
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 |
Early glomerular filtration defect and severe renal disease in podocin-deficient mice. | Roselli S | Molecular and cellular biology | 2004 | PMID: 14701729 |
Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis. | Caridi G | Journal of the American Society of Nephrology : JASN | 2001 | PMID: 11729243 |
NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. | Boute N | Nature genetics | 2000 | PMID: 10742096 |
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Text-mined citations for rs528833893 ...
HelpRecord last updated Apr 20, 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.