A heterozygous nonsense variant, NM_001009944.2(PKD1):c.12061C>T, has been identified in exon 44 of 46 of the PKD1 gene. The variant is predicted to result in a premature stop codon at position 4021 of the protein (NP_001009944.2(PKD1):p.(Arg4021*)), likely resulting in loss of protein function through truncation, which includes the PKD channel domain (Rossetti, S. et al., 1996). However, loss of function via NMD has not been excluded. The variant is absent in population databases (gnomAD, dbSNP, 1000G), however, it has been reported in at least three patients with kidney cysts and been shown to segregate with disease (Rossetti, S. et al., 1996). In addition, other heterozygous truncating variants located downstream have been reported as pathogenic in individuals with this condition (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
ClinVar Genomic variation as it relates to human health
NM_001009944.3(PKD1):c.12061C>T (p.Arg4021Ter)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001009944.3(PKD1):c.12061C>T (p.Arg4021Ter)
Variation ID: 636627 Accession: VCV000636627.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2090751 (GRCh38) [ NCBI UCSC ] 16: 2140752 (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 27, 2019 Aug 11, 2024 Jul 19, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001009944.3:c.12061C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001009944.3:p.Arg4021Ter nonsense NM_000296.4:c.12058C>T NP_000287.4:p.Arg4020Ter nonsense NC_000016.10:g.2090751G>A NC_000016.9:g.2140752G>A NG_005895.1:g.46446G>A NG_008617.1:g.52470C>T LRG_487:g.46446G>A - Protein change
- R4021*, R4020*
- Other names
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- Canonical SPDI
- NC_000016.10:2090750: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.
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- 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. |
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| PKD1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3777 | 4362 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2022 | RCV000788513.7 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2024 | RCV001251463.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001292276.3 |
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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Pathogenic
(Apr 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000927660.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019
Comment:
Patient analyzed with Polycystic Kidney Disease Panel
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Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: research
|
Polycystic kidney disease, adult type
Affected status: yes
Allele origin:
germline
|
Molecular Biology Laboratory, Fundació Puigvert
Study: KidneyPanel_2020
Accession: SCV001425156.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
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Pathogenic
(Jul 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease, adult type
Affected status: yes
Allele origin:
unknown
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001427163.2
First in ClinVar: Aug 13, 2020 Last updated: Sep 18, 2020 |
Comment:
A heterozygous nonsense variant, NM_001009944.2(PKD1):c.12061C>T, has been identified in exon 44 of 46 of the PKD1 gene. The variant is predicted to result in a … (more)
A heterozygous nonsense variant, NM_001009944.2(PKD1):c.12061C>T, has been identified in exon 44 of 46 of the PKD1 gene. The variant is predicted to result in a premature stop codon at position 4021 of the protein (NP_001009944.2(PKD1):p.(Arg4021*)), likely resulting in loss of protein function through truncation, which includes the PKD channel domain (Rossetti, S. et al., 1996). However, loss of function via NMD has not been excluded. The variant is absent in population databases (gnomAD, dbSNP, 1000G), however, it has been reported in at least three patients with kidney cysts and been shown to segregate with disease (Rossetti, S. et al., 1996). In addition, other heterozygous truncating variants located downstream have been reported as pathogenic in individuals with this condition (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Clinical Features:
Renal hypoplasia (disease) (present) , Multiple renal cysts (present)
Secondary finding: no
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Pathogenic
(Aug 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease, adult type
Affected status: yes
Allele origin:
germline
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(GEEPAD) Grupo de Estudio de la Enfermedad Poliquística Autosómica Dominante, Hospitales Universitarios Virgen de las Nieves y San Cecilio (Granada)
Accession: SCV002558710.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Number of individuals with the variant: 1
Age: >18 years
Geographic origin: Spain
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Pathogenic
(Aug 16, 2022)
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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: SCV001776815.3
First in ClinVar: Aug 13, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9044320, 24694054, 25525159, 8911610, 29633482, 22508176, 11115377, 22185115, 19686598, 32939031) (less)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease, adult type
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573077.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000636627 / PMID: 8911610 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Polycystic kidney disease (present) , Nephrocalcinosis (present)
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Pathogenic
(Jul 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease, adult type
Affected status: yes
Allele origin:
germline
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Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005184295.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
PM2_Supporting+PVS1+PS4_Moderate
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Polycystic Kidney disease
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001480961.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Comment:
The PKD1 p.Arg4021* variant was identified in 7 of 2636 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD and was not identified in … (more)
The PKD1 p.Arg4021* variant was identified in 7 of 2636 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD and was not identified in 200 control chromosomes from healthy individuals (Audrezet 2012, Rossetti 2001, Rossetti 2007, Yu 2011, Hwang 2016). The variant was also identified in LOVD 3.0 (1x) and ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in dbSNP, ClinVar, PKD1-LOVD, or the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Arg4021* variant leads to a premature stop codon at position 4021, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD1 gene are an established mechanism of disease in ADPKD and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
|
Comment:
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9044320, 24694054, 25525159, 8911610, 29633482, 22508176, 11115377, 22185115, 19686598, 32939031)
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000636627 / PMID: 8911610 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PM2_Supporting+PVS1+PS4_Moderate
Comment:
The PKD1 p.Arg4021* variant was identified in 7 of 2636 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD and was not identified in 200 control chromosomes from healthy individuals (Audrezet 2012, Rossetti 2001, Rossetti 2007, Yu 2011, Hwang 2016). The variant was also identified in LOVD 3.0 (1x) and ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in dbSNP, ClinVar, PKD1-LOVD, or the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Arg4021* variant leads to a premature stop codon at position 4021, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD1 gene are an established mechanism of disease in ADPKD and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
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:
A heterozygous nonsense variant, NM_001009944.2(PKD1):c.12061C>T, has been identified in exon 44 of 46 of the PKD1 gene. The variant is predicted to result in a premature stop codon at position 4021 of the protein (NP_001009944.2(PKD1):p.(Arg4021*)), likely resulting in loss of protein function through truncation, which includes the PKD channel domain (Rossetti, S. et al., 1996). However, loss of function via NMD has not been excluded. The variant is absent in population databases (gnomAD, dbSNP, 1000G), however, it has been reported in at least three patients with kidney cysts and been shown to segregate with disease (Rossetti, S. et al., 1996). In addition, other heterozygous truncating variants located downstream have been reported as pathogenic in individuals with this condition (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9044320, 24694054, 25525159, 8911610, 29633482, 22508176, 11115377, 22185115, 19686598, 32939031)
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000636627 / PMID: 8911610 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PM2_Supporting+PVS1+PS4_Moderate
Comment:
The PKD1 p.Arg4021* variant was identified in 7 of 2636 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD and was not identified in 200 control chromosomes from healthy individuals (Audrezet 2012, Rossetti 2001, Rossetti 2007, Yu 2011, Hwang 2016). The variant was also identified in LOVD 3.0 (1x) and ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in dbSNP, ClinVar, PKD1-LOVD, or the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Arg4021* variant leads to a premature stop codon at position 4021, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD1 gene are an established mechanism of disease in ADPKD and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. | Domingo-Gallego A | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2022 | PMID: 33532864 |
| Identification of novel mutations and risk assessment of Han Chinese patients with autosomal dominant polycystic kidney disease. | Zhang M | Nephrology (Carlton, Vic.) | 2019 | PMID: 29633482 |
| Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease. | Yu C | BMC medical genetics | 2011 | PMID: 22185115 |
| Autosomal dominant polycystic kidney disease (ADPKD) in an Italian family carrying a novel nonsense mutation and two missense changes in exons 44 and 45 of the PKD1 Gene. | Rossetti S | American journal of medical genetics | 1996 | PMID: 8911610 |
| Towards understanding the pathogenesis of SLE. | Fournié GJ | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 1996 | PMID: 8649614 |
Text-mined citations for rs764431330 ...
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 Sep 17, 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.