ClinVar Genomic variation as it relates to human health
NM_004646.4(NPHS1):c.2417C>A (p.Ala806Asp)
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.2417C>A (p.Ala806Asp)
Variation ID: 56473 Accession: VCV000056473.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.12 19: 35842468 (GRCh38) [ NCBI UCSC ] 19: 36333370 (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 Dec 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004646.4:c.2417C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004637.1:p.Ala806Asp missense NC_000019.10:g.35842468G>T NC_000019.9:g.36333370G>T NG_013356.2:g.31820C>A LRG_693:g.31820C>A LRG_693t1:c.2417C>A LRG_693p1:p.Ala806Asp O60500:p.Ala806Asp - Protein change
- A806D
- Other names
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- Canonical SPDI
- NC_000019.10:35842467:G: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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
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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NPHS1 | - | - |
GRCh38 GRCh37 |
1634 | 1813 |
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
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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 (7) |
criteria provided, multiple submitters, no conflicts
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Aug 25, 2023 | RCV000049886.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2023 | RCV000712426.8 |
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
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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 07, 2016)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: yes
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Study: Clinvar_gadteam_Clinical_exome_analysis_3
Accession: SCV000803816.1 First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
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Pathogenic
(Aug 22, 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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Illumina Laboratory Services, Illumina
Accession: SCV000915827.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The NPHS1 c.2417C>A (p.Ala806Asp) variant has been reported in at least five studies and is found in a homozygous state in three probands and in … (more)
The NPHS1 c.2417C>A (p.Ala806Asp) variant has been reported in at least five studies and is found in a homozygous state in three probands and in a compound heterozygous state in two probands with congenital Finnish nephrosis (Lenkerri et al. 1999; Santin et al. 2009; Santin et al. 2011; Lovric et al. 2014; Machuca et al. 2014; Berody et al. 2018). The p.Ala806Asp variant was absent from 30 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele so the variant is presumed to be rare. Immunostaining of cells with wildtype NPHS1 demonstrated expression at the plasma membrane, whereas in cells containing the p.Ala806Asp variant there was no detectable surface staining observed (Liu et al. 2001). Based on the evidence, the p.Ala806Asp variant is classified as pathogenic for congenital nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 30, 2019)
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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
Accession: SCV000842919.2
First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. Conflicting predictions of the effect on the protein. In multiple individuals, this … (more)
The frequency of this variant in the general population is consistent with pathogenicity. Conflicting predictions of the effect on the protein. 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. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
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Likely pathogenic
(Jun 12, 2014)
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criteria provided, single submitter
Method: literature only
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Finnish congenital nephrotic syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220399.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Sep 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: yes
Allele origin:
unknown
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Vasylyeva lab, Texas Tech University Health Sciences Center
Accession: SCV004123130.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
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Pathogenic
(Aug 25, 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: SCV004191424.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 14, 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: SCV001385277.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 806 of the NPHS1 protein … (more)
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 806 of the NPHS1 protein (p.Ala806Asp). This variant is present in population databases (rs386833912, gnomAD 0.002%). This missense change has been observed in individuals with congenital nephrotic syndrome (PMID: 9915943, 20507940, 21415313, 24742477, 33980730). ClinVar contains an entry for this variant (Variation ID: 56473). 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 NPHS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 11726550). This variant disrupts the p.Ala806 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23349334; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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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:
unknown
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082295.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
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Comment:
Converted during submission to Likely pathogenic.
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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: SCV001460528.1
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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Next-Generation Sequencing for Congenital Nephrotic Syndrome: A Multi-Center Cross-Sectional Study from India. | Joshi A | Indian pediatrics | 2021 | PMID: 33980730 |
Treatment and outcome of congenital nephrotic syndrome. | Bérody S | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2019 | PMID: 29474669 |
Rapid detection of monogenic causes of childhood-onset steroid-resistant nephrotic syndrome. | Lovric S | Clinical journal of the American Society of Nephrology : CJASN | 2014 | PMID: 24742477 |
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 |
Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. | Machuca E | Journal of the American Society of Nephrology : JASN | 2010 | PMID: 20507940 |
Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis. | Santín S | Kidney international | 2009 | PMID: 19812541 |
Defective nephrin trafficking caused by missense mutations in the NPHS1 gene: insight into the mechanisms of congenital nephrotic syndrome. | Liu L | Human molecular genetics | 2001 | PMID: 11726550 |
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 |
Text-mined citations for rs386833912 ...
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.