ClinVar Genomic variation as it relates to human health
NM_000297.4(PKD2):c.1774C>T (p.Arg592Ter)
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_000297.4(PKD2):c.1774C>T (p.Arg592Ter)
Variation ID: 477625 Accession: VCV000477625.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q22.1 4: 88056143 (GRCh38) [ NCBI UCSC ] 4: 88977295 (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 Dec 26, 2017 Feb 20, 2024 Feb 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000297.4:c.1774C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000288.1:p.Arg592Ter nonsense NR_156488.2:n.1873C>T non-coding transcript variant NC_000004.12:g.88056143C>T NC_000004.11:g.88977295C>T NG_008604.1:g.53476C>T - Protein change
- R592*
- Other names
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- Canonical SPDI
- NC_000004.12:88056142:C:T
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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.
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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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PKD2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
775 | 997 |
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
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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 (1) |
criteria provided, single submitter
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Feb 4, 2017 | RCV000556150.7 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001292157.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV001331141.5 |
Submissions - Germline
Classification
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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
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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
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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
(Oct 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 2
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001523096.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557470.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 2 (MIM#613095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are many likely pathogenic or pathogenic NMD-predicted variants that have been reported (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five individuals with polycystic kidney and/or liver disease (ClinVar; PMIDs: 22508176, 29378535, 32970388, 33569422). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 2
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841328.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was 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. This variant was 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: VCV000477625 / PMID: 22508176). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Proteinuria (present)
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Pathogenic
(Feb 04, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant polycystic kidney disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000658968.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal at codon 592 (p.Arg592*) of the PKD2 gene. It is expected to result in an absent … (more)
This sequence change creates a premature translational stop signal at codon 592 (p.Arg592*) of the PKD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKD2 are known to be pathogenic. This particular variant has been reported in the literature in two individuals affected with polycystic kidney disease (PMID: 22508176). For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV001480734.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Comment:
The PKD2 p.Arg592X variant was identified in 2 of 1400 proband chromosomes (frequency: 0.0014) from individuals or families with ADPKD (Audrézet 2012). The variant was … (more)
The PKD2 p.Arg592X variant was identified in 2 of 1400 proband chromosomes (frequency: 0.0014) from individuals or families with ADPKD (Audrézet 2012). The variant was also identified in ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in dbSNP, ClinVar, LOVD 3.0, or PKD1-LOVD databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Arg592X variant leads to a premature stop codon at position 592, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD2 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)
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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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Association of a novel PKHD1 mutation in a family with autosomal dominant polycystic liver disease. | Wang J | Annals of translational medicine | 2021 | PMID: 33569422 |
Disease causing property analyzation of variants in 12 Chinese families with polycystic kidney disease. | Dong K | Molecular genetics & genomic medicine | 2020 | PMID: 32970388 |
Whole exome sequencing reveals a stop-gain mutation of PKD2 in an autosomal dominant polycystic kidney disease family complicated with aortic dissection. | Zhang W | BMC medical genetics | 2018 | PMID: 29378535 |
Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. | Audrézet MP | Human mutation | 2012 | PMID: 22508176 |
Text-mined citations for rs1553926905 ...
HelpRecord last updated Apr 15, 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.