ClinVar Genomic variation as it relates to human health
NM_004646.4(NPHS1):c.2227C>T (p.Arg743Cys)
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.2227C>T (p.Arg743Cys)
Variation ID: 56469 Accession: VCV000056469.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.12 19: 35843579 (GRCh38) [ NCBI UCSC ] 19: 36334481 (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 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004646.4:c.2227C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004637.1:p.Arg743Cys missense NC_000019.10:g.35843579G>A NC_000019.9:g.36334481G>A NG_013356.2:g.30709C>T LRG_693:g.30709C>T LRG_693t1:c.2227C>T LRG_693p1:p.Arg743Cys O60500:p.Arg743Cys - Protein change
- R743C
- Other names
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- Canonical SPDI
- NC_000019.10:35843578:G: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
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
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. |
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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
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 (7) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000049882.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2024 | RCV000797708.8 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 22, 2018 | RCV001328086.1 |
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
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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
(Sep 14, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983586.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: NPHS1 c.2227C>T (p.Arg743Cys) results in a non-conservative amino acid change located in the Spacer region between Ig-6 and Ig-7 domains (Liu_2001) of the … (more)
Variant summary: NPHS1 c.2227C>T (p.Arg743Cys) results in a non-conservative amino acid change located in the Spacer region between Ig-6 and Ig-7 domains (Liu_2001) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251448 control chromosomes. c.2227C>T has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 (example, Lenkkeri_1999, Patrakka_2000, Liu_2001, Kari_2014, Bierzynska_2017, 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. The most pronounced variant effect results in ERAD (endoplasmic reticulum associated degradation) while not impacting trafficking to the cell surface (example, Drozova_2013, Miyai_2014, Yoshida_2021). Endoplasmic reticulum associated degradation is required for nephrin maturation and kidney glomerular filtration function (Yoshida_2021). Five 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 (n=1)/likely pathogenic (n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 03, 2016)
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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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Counsyl
Accession: SCV000485923.2
First in ClinVar: Jul 24, 2013 Last updated: Dec 24, 2022 |
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Likely pathogenic
(May 24, 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: SCV002775295.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Aug 14, 2023)
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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: SCV001771364.2
First in ClinVar: Aug 07, 2021 Last updated: Aug 24, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32377865, 24142548, 11726550, 24303155, 33591954, 9915943, 24902943, 35372954, 11854170, 33089377) (less)
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Likely pathogenic
(Oct 28, 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: SCV004191374.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: research
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Finnish congenital nephrotic syndrome
Affected status: yes
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV004232717.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Number of individuals with the variant: 1
Clinical Features:
Abnormality of skin pigmentation (present) , Limb hypertonia (present) , Seizure (present) , Abnormality of limbs (present) , Neonatal hypoglycemia (present) , Hypoglycemia (present) , … (more)
Abnormality of skin pigmentation (present) , Limb hypertonia (present) , Seizure (present) , Abnormality of limbs (present) , Neonatal hypoglycemia (present) , Hypoglycemia (present) , Hypertonia (present) (less)
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Pathogenic
(Jan 13, 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: SCV000937283.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 743 of the NPHS1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 743 of the NPHS1 protein (p.Arg743Cys). This variant is present in population databases (rs386833909, gnomAD 0.008%). This missense change has been observed in individuals with congenital nephrotic syndrome (PMID: 9915943, 10972661, 20172850, 20507940, 24902943, 28117080). ClinVar contains an entry for this variant (Variation ID: 56469). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHS1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NPHS1 function (PMID: 11726550, 24142548, 24303155). 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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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: SCV000082291.1
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
(Feb 22, 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: SCV001449378.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This individual is homozygous for the c.2227C>T p.(Arg743Cys) variant in the NPHS1 gene. This variant has been reported in the ExAC database (http://exac.broadinstitute.org) with a … (more)
This individual is homozygous for the c.2227C>T p.(Arg743Cys) variant in the NPHS1 gene. This variant has been reported in the ExAC database (http://exac.broadinstitute.org) with a very low allele frequency of 0.0016% (2 out of 121,386 alleles). It has also been reported in compound heterozygote state in mulitple patients with congenital nephrotic syndrome of Finnish type (see references). In addition, in vitro studies found that the p.Arg732Cys mutant peptide did not fold correctly and was rapidly degraded in the endoplasmic reticulum (Drozdova et al. 2013 Physiol Rep 1:e00086). In silico analysis of pathogenicity (through Alamut Visual v.2.8.1) using PolyPhen2, SIFT and MutationTaster all predict that this variant is likely to be pathogenic. This variant is considered to be pathogenic according to the ACMG guidelines. (less)
Number of individuals with the variant: 1
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Likely 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: SCV001460532.1
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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Endoplasmic reticulum-associated degradation is required for nephrin maturation and kidney glomerular filtration function. | Yoshida S | The Journal of clinical investigation | 2021 | PMID: 33591954 |
Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. | Bierzynska A | Kidney international | 2017 | PMID: 28117080 |
Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years. | Kari JA | Pediatric nephrology (Berlin, Germany) | 2014 | PMID: 24902943 |
Functional analysis of NPHS1 mutations in Japanese patients. | Miyai T | Histology and histopathology | 2014 | PMID: 24142548 |
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 |
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 |
Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients. | Patrakka J | Kidney international | 2000 | PMID: 10972661 |
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 |
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Text-mined citations for rs386833909 ...
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.