ClinVar Genomic variation as it relates to human health
NM_138694.4(PKHD1):c.11074C>T (p.Arg3692Ter)
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_138694.4(PKHD1):c.11074C>T (p.Arg3692Ter)
Variation ID: 593691 Accession: VCV000593691.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p12.3 6: 51659052 (GRCh38) [ NCBI UCSC ] 6: 51523850 (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 16, 2018 Jun 17, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138694.4:c.11074C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619639.3:p.Arg3692Ter nonsense NC_000006.12:g.51659052G>A NC_000006.11:g.51523850G>A NG_008753.1:g.433574C>T - Protein change
- R3692*
- Other names
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- Canonical SPDI
- NC_000006.12:51659051: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
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The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 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 | ||
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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
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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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PKHD1 | - | - |
GRCh38 GRCh37 |
5041 | 5256 |
Conditions - Germline
Condition
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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. |
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Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2017 | RCV000728802.4 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 27, 2023 | RCV001004187.13 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2021 | RCV001844843.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV003465658.2 |
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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Pathogenic
(Aug 16, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000856418.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163012.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Likely pathogenic
(Sep 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Laboratory of Molecular Genetics, Children's Memorial Health Institute
Accession: SCV001434240.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
Clinical Features:
Polycystic kidney disease (present) , Hepatic fibrosis (present) , Portal hypertension (present)
Age: 0-9 years
Sex: male
Geographic origin: Poland
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Pathogenic
(Jul 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002571029.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: PKHD1 c.11074C>T (p.Arg3692X) 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.11074C>T (p.Arg3692X) 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 allele was found at a frequency of 8e-06 in 251350 control chromosomes (gnomAD and publication data). c.11074C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (Furu_2003, Jung_2020, Wicher_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n-=4) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001396959.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg3692*) 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.Arg3692*) 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 593691). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 12874454). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Polycystic kidney disease 4
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051938.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004204557.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Sep 01, 2021)
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no assertion criteria provided
Method: research
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Autosomal dominant polycystic liver disease
Affected status: yes
Allele origin:
germline
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Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center
Accession: SCV001876975.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
Geographic origin: Belgium
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Pathogenic
(Aug 18, 2017)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002075493.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Occurrence of Portal Hypertension and Its Clinical Course in Patients With Molecularly Confirmed Autosomal Recessive Polycystic Kidney Disease (ARPKD). | Wicher D | Frontiers in pediatrics | 2020 | PMID: 33282801 |
Fatal outcome of autosomal recessive polycystic kidney disease in neonates with recessive PKHD1 mutations. | Jung J | Medicine | 2020 | PMID: 32384486 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Pilot study of expanded carrier screening for 11 recessive diseases in China: results from 10,476 ethnically diverse couples. | Zhao S | European journal of human genetics : EJHG | 2019 | PMID: 30275481 |
Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease. | Denamur E | Kidney international | 2010 | PMID: 19940839 |
Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. | Furu L | Journal of the American Society of Nephrology : JASN | 2003 | PMID: 12874454 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1 | - | - | - | - |
Text-mined citations for rs769559267 ...
HelpRecord last updated Sep 29, 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.