ClinVar Genomic variation as it relates to human health
NM_004646.4(NPHS1):c.3250dup (p.Val1084fs)
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_004646.4(NPHS1):c.3250dup (p.Val1084fs)
Variation ID: 56497 Accession: VCV000056497.29
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 19q13.12 19: 35831678-35831679 (GRCh38) [ NCBI UCSC ] 19: 36322580-36322581 (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 Jul 24, 2013 Feb 14, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004646.4:c.3250dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004637.1:p.Val1084fs frameshift NM_004646.3:c.3250dupG NC_000019.10:g.35831685dup NC_000019.9:g.36322587dup NG_013356.2:g.42609dup LRG_693:g.42609dup LRG_693t1:c.3250dup LRG_693p1:p.Val1084fs - Protein change
- V1084fs
- Other names
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- Canonical SPDI
- NC_000019.10:35831678:CCCCCCC:CCCCCCCC
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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.
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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
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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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NPHS1 | - | - |
GRCh38 GRCh37 |
1620 | 1797 |
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/Likely pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2023 | RCV000049910.16 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2024 | RCV000483335.11 | |
Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
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Aug 28, 2018 | RCV001328317.2 |
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 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917910.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: NPHS1 c.3250dupG (p.Val1084GlyfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NPHS1 c.3250dupG (p.Val1084GlyfsX12) 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 0.00023 in 82306 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.00023 vs 0.0034), allowing no conclusion about variant significance. c.3250dupG has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 (e.g. Heeringa 2008, Sadowski 2015). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 24, 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: SCV000568763.5
First in ClinVar: Apr 27, 2017 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: 23949594, 9660941, 19194555) (less)
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Likely pathogenic
(Apr 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV003935873.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
Clinical Features:
Congenital nephrotic syndrome (present) , Diffuse mesangial sclerosis (present)
Age: 0-9 years
Sex: female
Tissue: blood
Comment on evidence:
No parental testing. Unknown if patient is a true homozygote or there is a partial/full gene deletion present
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Pathogenic
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004191377.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018357.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 08, 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: SCV000964243.6
First in ClinVar: Aug 13, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val1084Glyfs*12) in the NPHS1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Val1084Glyfs*12) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). 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 nephrotic syndrome (PMID: 9660941, 19194555, 23949594, 28392951). ClinVar contains an entry for this variant (Variation ID: 56497). 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
(Jul 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002778711.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Finnish congenital nephrotic syndrome
Affected status: not provided
Allele origin:
not provided
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082319.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013 |
Comment:
Converted during submission to Likely pathogenic.
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Pathogenic
(Feb 09, 2017)
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no assertion criteria provided
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132442.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Pathogenic
(Jan 29, 2019)
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no assertion criteria provided
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132803.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
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Pathogenic
(Mar 26, 2019)
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no assertion criteria provided
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV001192689.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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Pathogenic
(Aug 28, 2018)
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no assertion criteria provided
Method: clinical testing
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Nephrotic syndrome
Affected status: yes
Allele origin:
unknown
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Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449376.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This patient is also heterozygous for a known pathogenic variant, c.3250dup, in the NPHS1 gene. This frameshifting variant (dbSNP: rs386833936) is predicted to create a … (more)
This patient is also heterozygous for a known pathogenic variant, c.3250dup, in the NPHS1 gene. This frameshifting variant (dbSNP: rs386833936) is predicted to create a premature stop codon 11 positions downstream (p.Val1084Glyfs*12), and may result in a null allele due to nonsense-mediated mRNA decay. This variant is considered to be pathogenic, and has been previously reported in patients with congenital nephrotic syndrome of Finnish type in the literature (Kestila et al 1998 Mol Cell 1:575-582; Lenkkeri et al 1999 Am J Hum Genet 64:51-61; Lee et al 2009 J Korean Med Sci 24:S210-S214). (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001456411.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930595.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965082.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Mar 01, 1998)
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no assertion criteria provided
Method: literature only
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NEPHROTIC SYNDROME, TYPE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027468.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 07, 2022 |
Comment on evidence:
In a North American patient with congenital nephrotic syndrome (256300), Kestila et al. (1998) identified a heterozygous 1-bp insertion (3250insG) in exon 24 of the … (more)
In a North American patient with congenital nephrotic syndrome (256300), Kestila et al. (1998) identified a heterozygous 1-bp insertion (3250insG) in exon 24 of the nephrin gene, resulting in a frameshift and premature termination. The other allele carried the Fin(minor) mutation (602716.0002). (less)
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Likely pathogenic
(Nov 10, 2017)
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no assertion criteria provided
Method: literature only
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Nephrotic syndrome
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106880.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 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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Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome. | Warejko JK | Clinical journal of the American Society of Nephrology : CJASN | 2018 | PMID: 29127259 |
Three Novel Mutations in the NPHS1 Gene in Vietnamese Patients with Congenital Nephrotic Syndrome. | Nguyen TK | Case reports in genetics | 2017 | PMID: 28392951 |
Congenital nephrotic syndrome with prolonged renal survival without renal replacement therapy. | Wong W | Pediatric nephrology (Berlin, Germany) | 2013 | PMID: 23949594 |
Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. | Machuca E | Journal of the American Society of Nephrology : JASN | 2010 | PMID: 20507940 |
Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS). | Schoeb DS | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2010 | PMID: 20172850 |
Two Korean infants with genetically confirmed congenital nephrotic syndrome of Finnish type. | Lee BH | Journal of Korean medical science | 2009 | PMID: 19194555 |
Thirteen novel NPHS1 mutations in a large cohort of children with congenital nephrotic syndrome. | Heeringa SF | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2008 | PMID: 18503012 |
Nephrin TRAP mice lack slit diaphragms and show fibrotic glomeruli and cystic tubular lesions. | Rantanen M | Journal of the American Society of Nephrology : JASN | 2002 | PMID: 12039988 |
Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. | Koziell A | Human molecular genetics | 2002 | PMID: 11854170 |
Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome. | Beltcheva O | Human mutation | 2001 | PMID: 11317351 |
Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations. | Lenkkeri U | American journal of human genetics | 1999 | PMID: 9915943 |
Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome. | Kestilä M | Molecular cell | 1998 | PMID: 9660941 |
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Text-mined citations for rs386833935 ...
HelpRecord last updated Mar 17, 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.