ClinVar Genomic variation as it relates to human health
NM_014625.4(NPHS2):c.948del (p.Ala317fs)
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.948del (p.Ala317fs)
Variation ID: 188990 Accession: VCV000188990.13
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 1q25.2 1: 179551377 (GRCh38) [ NCBI UCSC ] 1: 179520512 (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 Mar 29, 2015 Feb 14, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014625.4:c.948del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055440.1:p.Ala317fs frameshift NM_144696.6:c.3032-3135del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001297575.2:c.744del NP_001284504.1:p.Ala249fs frameshift NM_014625.3:c.948delT NC_000001.11:g.179551377del NC_000001.10:g.179520512del NG_007535.1:g.29573del NG_033075.1:g.190658del LRG_887:g.29573del LRG_887t1:c.948del LRG_887p1:p.Ala317fs - Protein change
- A317fs, A249fs
- Other names
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- Canonical SPDI
- NC_000001.11:179551376: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 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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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
Help
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 (4) |
criteria provided, multiple submitters, no conflicts
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Sep 2, 2023 | RCV000169369.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000517439.6 | |
Pathogenic (1) |
no assertion criteria provided
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Nov 6, 2020 | RCV001831989.1 |
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
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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
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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
(Nov 01, 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
Accession: SCV000614355.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Nov 19, 2018)
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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: SCV001168621.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
The c.948delT variant in the NPHS2 gene has been reported previously in the compound heterozygous state with a second NPHS2 variant in individuals with steroid-resistant … (more)
The c.948delT variant in the NPHS2 gene has been reported previously in the compound heterozygous state with a second NPHS2 variant in individuals with steroid-resistant nephrotic syndrome (Lowik et al., 2008; Kerti et al., 2013). The c.948delT variant causes a frameshift starting with codon Alanine 317, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 31 of the new reading frame, denoted p.Ala317LeufsX31. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 67 amino acids are lost and replaced with 30 incorrect amino acids. The c.948delT variant is observed in 1/24,024 (0.004%) alleles from individuals of African background and 4/276,734 (0.001%) total alleles in large population cohorts (Lek et al., 2016). We interpret c.948delT as a pathogenic variant. (less)
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Pathogenic
(May 17, 2020)
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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: SCV001370677.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: NPHS2 c.948delT (p.Ala317LeufsX31) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NPHS2 c.948delT (p.Ala317LeufsX31) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251028 control chromosomes. c.948delT has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 2, also known as Steroid-resistant nephrotic syndrome type 2 (example, Ruf_2004, Billing_2004, Hinkes_2008, Lwik_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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
(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: SCV004049244.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Pathogenic
(Sep 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: SCV004191543.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 27, 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: SCV001577973.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ala317Leufs*31) in the NPHS2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Ala317Leufs*31) in the NPHS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 67 amino acid(s) of the NPHS2 protein. This variant is present in population databases (rs775170915, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with steroid-resistant nephrotic syndrome (PMID: 14978175, 18443213, 23242530). This variant is also known as p.L347X. ClinVar contains an entry for this variant (Variation ID: 188990). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 02, 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: SCV000220744.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
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Pathogenic
(Nov 06, 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: SCV002090085.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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 p.V290M mutation in late-onset steroid-resistant nephrotic syndrome. | Kerti A | Pediatric nephrology (Berlin, Germany) | 2013 | PMID: 23242530 |
Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis. | Löwik M | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2008 | PMID: 18443213 |
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 |
Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). | Hinkes BG | Pediatrics | 2007 | PMID: 17371932 |
In vivo expression of podocyte slit diaphragm-associated proteins in nephrotic patients with NPHS2 mutation. | Zhang SY | Kidney international | 2004 | PMID: 15327385 |
NPHS2 mutation associated with recurrence of proteinuria after transplantation. | Billing H | Pediatric nephrology (Berlin, Germany) | 2004 | PMID: 15015071 |
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 |
Text-mined citations for rs775170915 ...
HelpRecord last updated May 08, 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.