ClinVar Genomic variation as it relates to human health
NM_004646.4(NPHS1):c.1868G>T (p.Cys623Phe)
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
-
NM_004646.4(NPHS1):c.1868G>T (p.Cys623Phe)
Variation ID: 56453 Accession: VCV000056453.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.12 19: 35845430 (GRCh38) [ NCBI UCSC ] 19: 36336332 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 8, 2024 Mar 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_004646.4:c.1868G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004637.1:p.Cys623Phe missense NC_000019.10:g.35845430C>A NC_000019.9:g.36336332C>A NG_013356.2:g.28858G>T LRG_693:g.28858G>T LRG_693t1:c.1868G>T LRG_693p1:p.Cys623Phe O60500:p.Cys623Phe - Protein change
- C623F
- Other names
- -
- Canonical SPDI
- NC_000019.10:35845429:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
NPHS1 | - | - |
GRCh38 GRCh37 |
1670 | 1853 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV000049866.20 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000811777.14 | |
Pathogenic (1) |
no assertion criteria provided
|
Jan 17, 2019 | RCV001849305.1 | |
NPHS1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 7, 2024 | RCV004751248.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004240961.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: NPHS1 c.1868G>T (p.Cys623Phe) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. … (more)
Variant summary: NPHS1 c.1868G>T (p.Cys623Phe) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250770 control chromosomes (gnomAD). c.1868G>T has been reported in the literature in multiple individuals affected with Nephrotic Syndrome (examples: Hinkes_2007, Schoeb_2010, Cooper_2018, Tan_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant disrupts the cell surface translocation of mutant protein (Cooper_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30212551, 17371932, 20172850, 28921387). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004191383.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Likely pathogenic
(Apr 08, 2014)
|
criteria provided, single submitter
Method: literature only
|
Finnish congenital nephrotic syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220231.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
Likely pathogenic
(Jul 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893523.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
Likely pathogenic
(Jun 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001825075.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Published in vitro functional studies demonstrated that C623F significantly impaired tyrosine phosphorylation and cell surface translocation of mutant protein (Cooper et al., 2018; Liu et … (more)
Published in vitro functional studies demonstrated that C623F significantly impaired tyrosine phosphorylation and cell surface translocation of mutant protein (Cooper et al., 2018; Liu et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18709391, 27019444, 11317351, 30212551, 20172850, 21415313, 11726550, 9915943, 30655312, 15503167, 28921387, 24902943, 20798252, 11854170, 15338398, 31589614, 19812541) (less)
|
|
Pathogenic
(Jan 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Finnish congenital nephrotic syndrome
Affected status: yes
Allele origin:
unknown
|
Vasylyeva lab, Texas Tech University Health Sciences Center
Accession: SCV004123128.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000952063.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 623 of the NPHS1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 623 of the NPHS1 protein (p.Cys623Phe). This variant is present in population databases (rs386833895, gnomAD 0.008%). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 11854170, 15338398, 18709391, 19812541, 20172850, 24902943). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56453). 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). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000411567.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The NPHS1 c.1868G>T (p.Cys623Phe) variant has been reported in six studies and is found in a total of eight patients with congenital Finnish nephrosis, including … (more)
The NPHS1 c.1868G>T (p.Cys623Phe) variant has been reported in six studies and is found in a total of eight patients with congenital Finnish nephrosis, including in one patient in a homozygous state, six patients (including a sibling pair) in a compound heterozygous state, and one patient in a heterozygous state in whom a second variant was not detected (Lenkkeri et al. 1999; Koziell et al. 2002; Schultheiss et al. 2004; Santin et al. 2009; Buscher et al. 2010; Schoeb et al. 2010). The p.Cys623Phe variant was absent from 173 controls but is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated impaired intracellular trafficking of the p.Cys623Phe variant protein with retention in the endoplasmic reticulum compared to localization of the wild type protein at the plasma membrane (Liu et al. 2001). Based on the collective evidence, the p.Cys623Phe 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)
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001460537.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
probable-pathogenic
(-)
|
no assertion criteria provided
Method: not provided
|
Finnish congenital nephrotic syndrome
Affected status: not provided
Allele origin:
unknown
|
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082275.1
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
|
Comment:
Converted during submission to Likely pathogenic.
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931748.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
Pathogenic
(Jan 17, 2019)
|
no assertion criteria provided
Method: literature only
|
Nephrotic syndrome
Affected status: yes
Allele origin:
germline
|
Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106565.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
|
|
Pathogenic
(Aug 07, 2024)
|
no assertion criteria provided
Method: clinical testing
|
NPHS1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005359946.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The NPHS1 c.1868G>T variant is predicted to result in the amino acid substitution p.Cys623Phe. This variant has been reported to be pathogenic for congenital nephrotic … (more)
The NPHS1 c.1868G>T variant is predicted to result in the amino acid substitution p.Cys623Phe. This variant has been reported to be pathogenic for congenital nephrotic syndrome due to impaired cell surface translocation (see for example, Lenkkeri et al. 1999. PubMed ID:9915943 and Mann et al. 2019. PubMed ID: 30655312; functional study at Liu et al. 2001. PubMed ID:11726550). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956158.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients. | Mann N | Journal of the American Society of Nephrology : JASN | 2019 | PMID: 30655312 |
Characterization of a novel disease-associated mutation within NPHS1 and its effects on nephrin phosphorylation and signaling. | Cooper CJ | PloS one | 2018 | PMID: 30212551 |
Analysis of 24 genes reveals a monogenic cause in 11.1% of cases with steroid-resistant nephrotic syndrome at a single center. | Tan W | Pediatric nephrology (Berlin, Germany) | 2018 | PMID: 28921387 |
Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years. | Kari JA | Pediatric nephrology (Berlin, Germany) | 2014 | PMID: 24902943 |
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 |
Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. | Büscher AK | Clinical journal of the American Society of Nephrology : CJASN | 2010 | PMID: 20798252 |
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 |
Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis. | Santín S | Kidney international | 2009 | PMID: 19812541 |
Genetic forms of nephrotic syndrome: a single-center experience in Brussels. | Ismaili K | Pediatric nephrology (Berlin, Germany) | 2009 | PMID: 18709391 |
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 |
No evidence for genotype/phenotype correlation in NPHS1 and NPHS2 mutations. | Schultheiss M | Pediatric nephrology (Berlin, Germany) | 2004 | PMID: 15338398 |
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 |
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 |
click to load more click to collapse |
Text-mined citations for rs386833895 ...
HelpRecord last updated Oct 13, 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.