Variant summary: PKHD1 c.10452dupT (p.Leu3485SerfsX18) 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 (eg. c.10637delT/p.Val3546fsX22, c.11314C>T/p.Arg3772X). The variant allele was found at a frequency of 4.1e-06 in 245374 control chromosomes. c.10452dupT has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease. 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. One clinical diagnostic laboratory classified this variant as likely pathogenic. Many truncation variants downstream have been reported in affected individuals, such as c.10639dupC, c.11339dupC, c.11408dupA, and c.11538dupT, suggesting the functional importance of the C-terminal region of this protein. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_138694.4(PKHD1):c.10452dup (p.Leu3485fs)
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.
(8)
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/Likely pathogenic
8
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.10452dup (p.Leu3485fs)
Variation ID: 189084 Accession: VCV000189084.20
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 6p12.3 6: 51659673-51659674 (GRCh38) [ NCBI UCSC ] 6: 51524471-51524472 (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 Mar 29, 2015 Jun 17, 2024 Feb 15, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_138694.4:c.10452dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619639.3:p.Leu3485fs frameshift NM_138694.3:c.10452dup NC_000006.12:g.51659679dup NC_000006.11:g.51524477dup NG_008753.1:g.432952dup - Protein change
- L3485fs
- Other names
- -
- Canonical SPDI
- NC_000006.12:51659673:AAAAAA:AAAAAAA
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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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- 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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 9, 2023 | RCV000169490.14 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 15, 2024 | RCV002492694.3 |
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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Likely pathogenic
(Dec 10, 2014)
|
criteria provided, single submitter
Method: literature only
|
Polycystic kidney disease, infantile type
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220944.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Feb 02, 2018)
|
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: SCV000918006.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PKHD1 c.10452dupT (p.Leu3485SerfsX18) 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.10452dupT (p.Leu3485SerfsX18) 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 (eg. c.10637delT/p.Val3546fsX22, c.11314C>T/p.Arg3772X). The variant allele was found at a frequency of 4.1e-06 in 245374 control chromosomes. c.10452dupT has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease. 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. One clinical diagnostic laboratory classified this variant as likely pathogenic. Many truncation variants downstream have been reported in affected individuals, such as c.10639dupC, c.11339dupC, c.11408dupA, and c.11538dupT, suggesting the functional importance of the C-terminal region of this protein. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 16, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: yes
Allele origin:
inherited
|
Department of Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV001334117.1
First in ClinVar: Jul 05, 2020 Last updated: Jul 05, 2020 |
Comment on evidence:
in trans with deletion involving PKHD1 exons 1 - 52
|
|
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Pathogenic
(Nov 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002788218.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Sep 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Autosomal recessive polycystic kidney disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000946312.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189084). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189084). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15108281, 19914852). This variant is present in population databases (rs771623148, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Leu3485Serfs*18) 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). (less)
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Pathogenic
(Feb 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204539.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Jul 28, 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
|
Natera, Inc.
Accession: SCV002075513.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
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Pathogenic
(Jan 17, 2019)
|
no assertion criteria provided
Method: literature only
|
Autosomal recessive polycystic kidney disease
Affected status: yes
Allele origin:
germline
|
Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106573.1 First in ClinVar: Mar 23, 2022 Last updated: Mar 23, 2022 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189084). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15108281, 19914852). This variant is present in population databases (rs771623148, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Leu3485Serfs*18) 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).
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:
Variant summary: PKHD1 c.10452dupT (p.Leu3485SerfsX18) 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 (eg. c.10637delT/p.Val3546fsX22, c.11314C>T/p.Arg3772X). The variant allele was found at a frequency of 4.1e-06 in 245374 control chromosomes. c.10452dupT has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease. 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. One clinical diagnostic laboratory classified this variant as likely pathogenic. Many truncation variants downstream have been reported in affected individuals, such as c.10639dupC, c.11339dupC, c.11408dupA, and c.11538dupT, suggesting the functional importance of the C-terminal region of this protein. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189084). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15108281, 19914852). This variant is present in population databases (rs771623148, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Leu3485Serfs*18) 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).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels. | Yuan B | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32576985 |
| Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients. | Mann N | Journal of the American Society of Nephrology : JASN | 2019 | PMID: 30655312 |
| Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease. | Denamur E | Kidney international | 2010 | PMID: 19940839 |
| PKHD1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and congenital hepatic fibrosis. | Gunay-Aygun M | Molecular genetics and metabolism | 2010 | PMID: 19914852 |
| PKHD1 mutations in families requesting prenatal diagnosis for autosomal recessive polycystic kidney disease (ARPKD). | Bergmann C | Human mutation | 2004 | PMID: 15108281 |
| PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). | Bergmann C | Human mutation | 2004 | PMID: 15108277 |
Text-mined citations for rs771623148 ...
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 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.