Variant summary: NPHS2 c.643C>T (p.Gln215X) 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 1.2e-05 in 251220 control chromosomes (gnomAD). c.643C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nephrotic Syndrome (e.g. Machuca_2009, Jain_2014, Sadowski_2015, Feltran_2017). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic / likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_014625.4(NPHS2):c.643C>T (p.Gln215Ter)
Germline
Classification
Help
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.
(8)
Help
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.
Pathogenic/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_014625.4(NPHS2):c.643C>T (p.Gln215Ter)
Variation ID: 370159 Accession: VCV000370159.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q25.2 1: 179557122 (GRCh38) [ NCBI UCSC ] 1: 179526257 (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 Jan 7, 2017 Jun 17, 2024 Mar 19, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014625.4:c.643C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055440.1:p.Gln215Ter nonsense NM_001297575.2:c.534+2557C>T intron variant NC_000001.11:g.179557122G>A NC_000001.10:g.179526257G>A NG_007535.1:g.23828C>T LRG_887:g.23828C>T LRG_887t1:c.643C>T LRG_887p1:p.Gln215Ter - Protein change
- Q215*
- Other names
- -
- Canonical SPDI
- NC_000001.11:179557121: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
- Links
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. |
|||
| NPHS2 | - | - |
GRCh38 GRCh37 |
370 | 599 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 19, 2024 | RCV000409295.7 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 23, 2023 | RCV000712438.7 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 7, 2021 | RCV001828370.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Oct 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000842932.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
|
Pathogenic
(May 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Idiopathic nephrotic syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360830.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: NPHS2 c.643C>T (p.Gln215X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NPHS2 c.643C>T (p.Gln215X) 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 1.2e-05 in 251220 control chromosomes (gnomAD). c.643C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nephrotic Syndrome (e.g. Machuca_2009, Jain_2014, Sadowski_2015, Feltran_2017). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic / likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Dec 07, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Nephrotic syndrome, type 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000485402.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Apr 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Nephrotic syndrome, type 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002795597.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Nephrotic syndrome, type 2
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004049271.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
|
|
|
Pathogenic
(May 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001581819.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (no rsID available, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an … (more)
This variant is present in population databases (no rsID available, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370159). This premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 18823551, 25852895, 28658201). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Gln215*) in the NPHS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS2 are known to be pathogenic (PMID: 10742096, 14701729, 15253708, 23595123). (less)
|
|
|
Pathogenic
(Mar 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Nephrotic syndrome, type 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004191542.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 07, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Steroid-resistant nephrotic syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002090089.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
Comment:
This variant is present in population databases (no rsID available, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370159). This premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 18823551, 25852895, 28658201). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Gln215*) in the NPHS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS2 are known to be pathogenic (PMID: 10742096, 14701729, 15253708, 23595123).
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. |
Comment:
Variant summary: NPHS2 c.643C>T (p.Gln215X) 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 1.2e-05 in 251220 control chromosomes (gnomAD). c.643C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nephrotic Syndrome (e.g. Machuca_2009, Jain_2014, Sadowski_2015, Feltran_2017). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic / likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant is present in population databases (no rsID available, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370159). This premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 18823551, 25852895, 28658201). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Gln215*) in the NPHS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS2 are known to be pathogenic (PMID: 10742096, 14701729, 15253708, 23595123).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Targeted Next-Generation Sequencing in Brazilian Children With Nephrotic Syndrome Submitted to Renal Transplant. | Feltran LS | Transplantation | 2017 | PMID: 28658201 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. | Sadowski CE | Journal of the American Society of Nephrology : JASN | 2015 | PMID: 25349199 |
| Steroid-resistant nephrotic syndrome with mutations in NPHS2 (podocin): report from a three-generation family. | Jain V | Clinical kidney journal | 2014 | PMID: 25852895 |
| Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. | Tory K | Nature genetics | 2014 | PMID: 24509478 |
| NPHS2 mutations in steroid-resistant nephrotic syndrome: a mutation update and the associated phenotypic spectrum. | Bouchireb K | Human mutation | 2014 | PMID: 24227627 |
| A molecular genetic analysis of childhood nephrotic syndrome in a cohort of Saudi Arabian families. | Al-Hamed MH | Journal of human genetics | 2013 | PMID: 23595123 |
| Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant. | Machuca E | Kidney international | 2009 | PMID: 19145239 |
| NPHS2 variation in focal and segmental glomerulosclerosis. | Tonna SJ | BMC nephrology | 2008 | PMID: 18823551 |
| NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. | Weber S | Kidney international | 2004 | PMID: 15253708 |
| Early glomerular filtration defect and severe renal disease in podocin-deficient mice. | Roselli S | Molecular and cellular biology | 2004 | PMID: 14701729 |
| NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. | Boute N | Nature genetics | 2000 | PMID: 10742096 |
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Text-mined citations for rs778055996 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 13, 2025
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.