ClinVar Genomic variation as it relates to human health
NM_004646.4(NPHS1):c.1096A>C (p.Ser366Arg)
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.1096A>C (p.Ser366Arg)
Variation ID: 56420 Accession: VCV000056420.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.12 19: 35848711 (GRCh38) [ NCBI UCSC ] 19: 36339613 (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 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004646.4:c.1096A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004637.1:p.Ser366Arg missense NC_000019.10:g.35848711T>G NC_000019.9:g.36339613T>G NG_013356.2:g.25577A>C NG_051206.1:g.2077T>G LRG_693:g.25577A>C LRG_693t1:c.1096A>C LRG_693p1:p.Ser366Arg O60500:p.Ser366Arg - Protein change
- S366R
- Other names
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- Canonical SPDI
- NC_000019.10:35848710:T:G
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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 0.00000
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 |
1634 | 1813 |
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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Sep 24, 2023 | RCV000049833.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 15, 2023 | RCV001065065.4 |
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
(Sep 24, 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: SCV004191399.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 15, 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: SCV001230004.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 366 of the NPHS1 protein (p.Ser366Arg). … (more)
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 366 of the NPHS1 protein (p.Ser366Arg). This variant is present in population databases (rs386833864, gnomAD 0.0009%). This missense change has been observed in individuals with NPHS1-related conditions (PMID: 9915943, 18709391, 20172850, 24371179, 24397250). ClinVar contains an entry for this variant (Variation ID: 56420). 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 95%. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 11726550, 18614772, 24303155). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 26, 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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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367536.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PP2,PP3,PP4.
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Pathogenic
(Feb 11, 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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810270.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 27, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922945.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: NPHS1 c.1096A>C (p.Ser366Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Five … (more)
Variant summary: NPHS1 c.1096A>C (p.Ser366Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1096A>C has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 (e.g., Lenkkeri_1999, Machuca_2010). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant disrupts protein localization and folding leading to retention and eventual degradation in the endoplasmic reticulum (e.g., Liu_2001, Drozova_2013, Yoshida_2021). Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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:
not provided
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082242.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: 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
(May 21, 2021)
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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: SCV002087091.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Endoplasmic reticulum-associated degradation is required for nephrin maturation and kidney glomerular filtration function. | Yoshida S | The Journal of clinical investigation | 2021 | PMID: 33591954 |
Mechanism of cystogenesis in nephrotic kidneys: a histopathological study. | Saraga M | BMC nephrology | 2014 | PMID: 24397250 |
Novel and known nephrin gene (NPHS1) mutations in two Greek cases with congenital nephrotic syndrome including a complex genotype. | Fylaktou I | Journal of genetics | 2013 | PMID: 24371179 |
Nephrin missense mutations: induction of endoplasmic reticulum stress and cell surface rescue by reduction in chaperone interactions. | Drozdova T | Physiological reports | 2013 | PMID: 24303155 |
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 |
Genetic forms of nephrotic syndrome: a single-center experience in Brussels. | Ismaili K | Pediatric nephrology (Berlin, Germany) | 2009 | PMID: 18709391 |
Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome. | Philippe A | Journal of the American Society of Nephrology : JASN | 2008 | PMID: 18614772 |
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 rs386833864 ...
HelpRecord last updated Feb 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.