ClinVar Genomic variation as it relates to human health
NM_138694.4(PKHD1):c.7264T>G (p.Cys2422Gly)
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.
Pathogenic(1); Likely pathogenic(6); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_138694.4(PKHD1):c.7264T>G (p.Cys2422Gly)
Variation ID: 406887 Accession: VCV000406887.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p12.2 6: 51747977 (GRCh37) [ NCBI UCSC ] 6: 51883179 (GRCh38) [ 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 Apr 17, 2017 Apr 15, 2024 Feb 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138694.4:c.7264T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619639.3:p.Cys2422Gly missense NM_170724.3:c.7264T>G NP_733842.2:p.Cys2422Gly missense NC_000006.12:g.51883179A>C NC_000006.11:g.51747977A>C NG_008753.1:g.209447T>G - Protein change
- C2422G
- Other names
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- Canonical SPDI
- NC_000006.12:51883178:A:C
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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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0.00060 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
Trans-Omics for Precision Medicine (TOPMed) 0.00074
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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PKHD1 | - | - |
GRCh38 GRCh37 |
4912 | 5123 |
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
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
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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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jun 1, 2023 | RCV000457585.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 1, 2023 | RCV000729736.13 | |
Uncertain significance (1) |
no assertion criteria provided
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Sep 1, 2021 | RCV001844833.1 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2023 | RCV003334387.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 21, 2024 | RCV003942478.1 |
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
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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
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
(Apr 27, 2018)
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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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Counsyl
Accession: SCV000799602.1
First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017 |
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Uncertain significance
(Oct 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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Eurofins Ntd Llc (ga)
Accession: SCV000857423.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Aug 21, 2018)
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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: SCV000915170.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The PKHD1 c.7264T>G (p.Cys2422Gly) missense variant has been reported in two studies and found in a total of four individuals with autosomal recessive polycystic kidney … (more)
The PKHD1 c.7264T>G (p.Cys2422Gly) missense variant has been reported in two studies and found in a total of four individuals with autosomal recessive polycystic kidney disease, including three individuals from two families in a compound heterozygous state and one neonate in a heterozygous state in whom a second variant was not identified (Furu et al. 2003; Bergmann et al. 2005). In all the three compound heterozygous individuals, the p.Cys2422Gly variant was found in trans with an established pathogenic variant, p.Thr36Met. The p.Cys2422Gly variant was absent from a total of 360 controls and is reported at a frequency of 0.00378 in the European (Finnish) population of the Exome Aggregation Consortium. One homozygote is reported in the European (Finnish) population of the Genome Aggregation Database. The evidence for this variant is limited. The p.Cys2422Gly variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(Oct 24, 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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Invitae
Accession: SCV000545843.4
First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 2422 of the PKHD1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 2422 of the PKHD1 protein (p.Cys2422Gly). This variant is present in population databases (rs201881567, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with PKHD1-related conditions (PMID: 12874454, 15698423, 20413436, 26489029, 33940108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406887). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Jun 01, 2023)
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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: SCV001989324.4
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14741187, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14741187, 20413436, 34405919, 26489029, 27752906, 12874454, 33940108, 15698423) (less)
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Likely pathogenic
(Jun 01, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547681.2
First in ClinVar: Jul 17, 2022 Last updated: Jul 29, 2023 |
Comment:
Variant summary: PKHD1 c.7264T>G (p.Cys2422Gly) results in a non-conservative amino acid change located in the Parallel beta-helix repeat (IPR006626) of the encoded protein sequence. Four … (more)
Variant summary: PKHD1 c.7264T>G (p.Cys2422Gly) results in a non-conservative amino acid change located in the Parallel beta-helix repeat (IPR006626) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 251278 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0005 vs 0.0071), allowing no conclusion about variant significance. c.7264T>G has been reported in the literature in multiple compound heterozygous individuals affected with Polycystic Kidney And Hepatic Disease and was found to segregate with disease in affected families (e.g. Furu_2003, Bergmann_2005, Braun_2016, Burgmaier_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same amino acid residue has been classified pathogenic in ClinVar, this suggests that this residue may be functionally critical for normal protein function (CV ID 1494871). The following publications have been ascertained in the context of this evaluation (PMID: 15698423, 26489029, 33940108, 12874454). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jan 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: yes
Allele origin:
germline
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Human Genetics Bochum, Ruhr University Bochum
Accession: SCV004042806.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
ACMG criteria used to clasify this variant: PM3, PM5, PP3_MOD
Clinical Features:
Renal cyst (present)
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Likely pathogenic
(Oct 31, 2023)
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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: SCV004204032.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Sep 15, 2022)
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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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Revvity Omics, Revvity
Accession: SCV004238586.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Feb 21, 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: SCV004762649.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The PKHD1 c.7264T>G variant is predicted to result in the amino acid substitution p.Cys2422Gly. In the compound heterozygous state with different pathogenic PKHD1 variants, this … (more)
The PKHD1 c.7264T>G variant is predicted to result in the amino acid substitution p.Cys2422Gly. In the compound heterozygous state with different pathogenic PKHD1 variants, this variant has been reported in unrelated individuals with autosomal recessive polycystic kidney disease (ARPKD) (Furu et al. 2003. PubMed ID: 12874454; Bergmann et al. 2005. PubMed ID: 15698423; Supplementary Table 2 at Braun et al. 2016. PubMed ID: 26489029). Of note, a different change affecting the same codon (c.7264T>C, p.Cys2422Arg) has also been reported in an ARPKD individual (Gunay-Aygun et al. 2010. PubMed ID: 19914852). In summary, the c.7264T>G (p.Cys2422Gly) variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(Oct 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004163597.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
PKHD1: PM3:Strong, PM2, PM5
Number of individuals with the variant: 1
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Uncertain significance
(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: SCV001876982.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
Sex: male
Geographic origin: Netherlands
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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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Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants. | Burgmaier K | Kidney international | 2021 | PMID: 33940108 |
Genetic analysis of the PKHD1 gene with long-rang PCR sequencing. | Tong YQ | Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban | 2016 | PMID: 27752906 |
Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity. | Braun DA | Kidney international | 2016 | PMID: 26489029 |
Correlation of kidney function, volume and imaging findings, and PKHD1 mutations in 73 patients with autosomal recessive polycystic kidney disease. | Gunay-Aygun M | Clinical journal of the American Society of Nephrology : CJASN | 2010 | PMID: 20413436 |
Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). | Bergmann C | Kidney international | 2005 | PMID: 15698423 |
Molecular genetics of autosomal recessive polycystic kidney disease. | Harris PC | Molecular genetics and metabolism | 2004 | PMID: 14741187 |
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 rs201881567 ...
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.