ClinVar Genomic variation as it relates to human health
NM_138694.4(PKHD1):c.7675G>C (p.Val2559Leu)
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.
Uncertain significance(5); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_138694.4(PKHD1):c.7675G>C (p.Val2559Leu)
Variation ID: 197602 Accession: VCV000197602.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p12.2 6: 51867921 (GRCh38) [ NCBI UCSC ] 6: 51732719 (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 15, 2018 May 1, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138694.4:c.7675G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619639.3:p.Val2559Leu missense NM_170724.3:c.7675G>C NP_733842.2:p.Val2559Leu missense NC_000006.12:g.51867921C>G NC_000006.11:g.51732719C>G NG_008753.1:g.224705G>C - Protein change
- V2559L
- Other names
- -
- Canonical SPDI
- NC_000006.12:51867920:C:G
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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.
The Genome Aggregation Database (gnomAD) 0.00070
Trans-Omics for Precision Medicine (TOPMed) 0.00092
The Genome Aggregation Database (gnomAD), exomes 0.00103
Exome Aggregation Consortium (ExAC) 0.00111
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00169
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
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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PKHD1 | - | - |
GRCh38 GRCh37 |
4912 | 5123 |
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. |
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Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2018 | RCV000178676.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 27, 2024 | RCV000806672.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV001358740.3 | |
Likely benign (1) |
no assertion criteria provided
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Sep 1, 2021 | RCV001844817.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 2, 2023 | RCV003352795.2 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV003977466.1 |
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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Uncertain significance
(Dec 12, 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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Blueprint Genetics
Accession: SCV000927493.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019
Comment:
Patient analyzed with Polycystic Kidney Disease Panel
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Likely benign
(Jan 27, 2024)
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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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Invitae
Accession: SCV000946685.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
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Likely benign
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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PKHD1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004795668.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(Mar 15, 2018)
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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: SCV000230801.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 8
Sex: mixed
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Uncertain significance
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001320060.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jan 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001554588.3
First in ClinVar: Apr 13, 2021 Last updated: Mar 30, 2024 |
Comment:
Variant summary: PKHD1 c.7675G>C (p.Val2559Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: PKHD1 c.7675G>C (p.Val2559Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 1613106 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0012 vs 0.0071), allowing no conclusion about variant significance. c.7675G>C has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease without strong evidence for causality (e.g. Sharp_2005, Tavira_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15805161, 25701400). ClinVar contains an entry for this variant (Variation ID: 197602). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004054814.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The c.7675G>C (p.V2559L) alteration is located in exon 48 (coding exon 47) of the PKHD1 gene. This alteration results from a G to C substitution … (more)
The c.7675G>C (p.V2559L) alteration is located in exon 48 (coding exon 47) of the PKHD1 gene. This alteration results from a G to C substitution at nucleotide position 7675, causing the valine (V) at amino acid position 2559 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Likely benign
(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: SCV001877014.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
Sex: female
Geographic origin: Netherlands
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930057.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Uncertain significance
(Mar 26, 2018)
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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: SCV001455249.1
First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964007.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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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A labor and cost effective next generation sequencing of PKHD1 in autosomal recessive polycystic kidney disease patients. | Tavira B | Gene | 2015 | PMID: 25701400 |
Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. | Sharp AM | Journal of medical genetics | 2005 | PMID: 15805161 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1 | - | - | - | - |
Text-mined citations for rs150046042 ...
HelpRecord last updated May 08, 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.