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: 32574212, 31730820)
ClinVar Genomic variation as it relates to human health
NM_138694.4(PKHD1):c.2725C>T (p.Arg909Ter)
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.
(10)
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
10
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_138694.4(PKHD1):c.2725C>T (p.Arg909Ter)
Variation ID: 167491 Accession: VCV000167491.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p12.2 6: 52043721 (GRCh38) [ NCBI UCSC ] 6: 51908519 (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 Jun 28, 2015 Oct 8, 2024 Mar 16, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_138694.4:c.2725C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619639.3:p.Arg909Ter nonsense NM_170724.3:c.2725C>T NP_733842.2:p.Arg909Ter nonsense NC_000006.12:g.52043721G>A NC_000006.11:g.51908519G>A NG_008753.1:g.48905C>T - Protein change
- R909*
- Other names
- -
- Canonical SPDI
- NC_000006.12:52043720: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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The Genome Aggregation Database (gnomAD) 0.00001
- 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. |
|||
| PKHD1 | - | - |
GRCh38 GRCh37 |
5054 | 5269 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 19, 2024 | RCV000176696.12 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 28, 2022 | RCV000790818.5 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 16, 2024 | RCV001781495.10 | |
|
PKHD1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
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Feb 5, 2024 | RCV003917507.2 |
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
(Dec 13, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000228393.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163053.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
|
|
Pathogenic
(Mar 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204664.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Nov 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002759201.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
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: 32574212, 31730820) (less)
|
|
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Pathogenic
(Oct 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811538.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Feb 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918010.2
First in ClinVar: Jun 02, 2019 Last updated: Mar 26, 2023 |
Comment:
Variant summary: PKHD1 c.2725C>T (p.Arg909X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PKHD1 c.2725C>T (p.Arg909X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251142 control chromosomes (gnomAD). c.2725C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (examples: Liang_2020, Obeidova_2020, Ajiri_2022,Ishiko_2022). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Aug 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018818.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000937061.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg909*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg909*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 167491). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Nov 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060147.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_138694.3(PKHD1):c.2725C>T(R909*) is a nonsense variant classified as pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. R909* has been observed in cases with … (more)
NM_138694.3(PKHD1):c.2725C>T(R909*) is a nonsense variant classified as pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. R909* has been observed in cases with relevant disease (PMID: 31730820, 32574212). Functional assessments of this variant are not available in the literature. R909* has not been observed in population frequency databases. In summary, NM_138694.3(PKHD1):c.2725C>T(R909*) is a nonsense variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
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Pathogenic
(Feb 05, 2024)
|
no assertion criteria provided
Method: clinical testing
|
PKHD1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004728745.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The PKHD1 c.2725C>T variant is predicted to result in premature protein termination (p.Arg909*). This variant has been reported to be pathogenic for autosomal recessive polycystic … (more)
The PKHD1 c.2725C>T variant is predicted to result in premature protein termination (p.Arg909*). This variant has been reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (Liang et al. 2019. PubMed ID: 31730820). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
Variant summary: PKHD1 c.2725C>T (p.Arg909X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251142 control chromosomes (gnomAD). c.2725C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (examples: Liang_2020, Obeidova_2020, Ajiri_2022,Ishiko_2022). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg909*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 167491). For these reasons, this variant has been classified as Pathogenic.
Comment:
NM_138694.3(PKHD1):c.2725C>T(R909*) is a nonsense variant classified as pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. R909* has been observed in cases with relevant disease (PMID: 31730820, 32574212). Functional assessments of this variant are not available in the literature. R909* has not been observed in population frequency databases. In summary, NM_138694.3(PKHD1):c.2725C>T(R909*) is a nonsense variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The PKHD1 c.2725C>T variant is predicted to result in premature protein termination (p.Arg909*). This variant has been reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (Liang et al. 2019. PubMed ID: 31730820). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in PKHD1 are expected to be pathogenic. This variant is interpreted 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:
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: 32574212, 31730820)
Comment:
Variant summary: PKHD1 c.2725C>T (p.Arg909X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251142 control chromosomes (gnomAD). c.2725C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (examples: Liang_2020, Obeidova_2020, Ajiri_2022,Ishiko_2022). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg909*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 167491). For these reasons, this variant has been classified as Pathogenic.
Comment:
NM_138694.3(PKHD1):c.2725C>T(R909*) is a nonsense variant classified as pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. R909* has been observed in cases with relevant disease (PMID: 31730820, 32574212). Functional assessments of this variant are not available in the literature. R909* has not been observed in population frequency databases. In summary, NM_138694.3(PKHD1):c.2725C>T(R909*) is a nonsense variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The PKHD1 c.2725C>T variant is predicted to result in premature protein termination (p.Arg909*). This variant has been reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (Liang et al. 2019. PubMed ID: 31730820). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotypic Variability in Siblings With Autosomal Recessive Polycystic Kidney Disease. | Ajiri R | Kidney international reports | 2022 | PMID: 35812281 |
| Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes. | Ishiko S | Clinical and experimental nephrology | 2022 | PMID: 34536170 |
| Results of targeted next-generation sequencing in children with cystic kidney diseases often change the clinical diagnosis. | Obeidova L | PloS one | 2020 | PMID: 32574212 |
| 28 novel mutations identified from 33 Chinese patients with cilia-related kidney disorders. | Liang N | Clinica chimica acta; international journal of clinical chemistry | 2020 | PMID: 31730820 |
| Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease. | Denamur E | Kidney international | 2010 | PMID: 19940839 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1 | - | - | - | - |
Text-mined citations for rs727504089 ...
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 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.