ClinVar Genomic variation as it relates to human health
NM_138694.4(PKHD1):c.1342G>C (p.Gly448Arg)
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(6); 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.1342G>C (p.Gly448Arg)
Variation ID: 374479 Accession: VCV000374479.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p12.2 6: 52058493 (GRCh38) [ NCBI UCSC ] 6: 51923291 (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 Aug 5, 2018 Oct 8, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138694.4:c.1342G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619639.3:p.Gly448Arg missense NM_170724.3:c.1342G>C NP_733842.2:p.Gly448Arg missense NC_000006.12:g.52058493C>G NC_000006.11:g.51923291C>G NG_008753.1:g.34133G>C - Protein change
- G448R
- Other names
- -
- Canonical SPDI
- NC_000006.12:52058492: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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0.00100 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00100
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00146
The Genome Aggregation Database (gnomAD) 0.00146
Trans-Omics for Precision Medicine (TOPMed) 0.00153
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 |
5031 | 5245 |
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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Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Feb 23, 2021 | RCV000415990.19 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000669988.18 | |
PKHD1-related disorder
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Likely benign (1) |
no assertion criteria provided
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Sep 25, 2024 | RCV003922678.2 |
Uncertain significance (1) |
no assertion criteria provided
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Sep 1, 2021 | RCV001844830.1 |
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
(Oct 17, 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:
unknown
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Counsyl
Accession: SCV000794795.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Jan 30, 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: SCV000704763.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 8
Sex: mixed
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Uncertain significance
(Oct 31, 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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Fulgent Genetics, Fulgent Genetics
Accession: SCV000897302.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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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: SCV001321980.1
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(May 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: no
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251895.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Likely benign
(Feb 23, 2021)
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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: SCV001803854.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 29642553, 25646624, 28492530, 26489027, 15805161, 21228398, 15698423)
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Uncertain significance
(Oct 31, 2016)
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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: SCV000493239.7
First in ClinVar: Jan 30, 2017 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 2
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Likely benign
(Jan 31, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001000747.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Uncertain significance
(May 08, 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: SCV001463515.1
First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551478.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PKHD1 p.Gly448Arg variant was identified in 4 of 618 proband chromosomes (frequency: 0.0065) from individuals with polycystic kidney disease (Eisenberger_2015_PMID:25646624; Bergmann_2005_PMID:15698423; Vora_2017_PMID:28518170; Sharp_2005_PMID:15805161). The … (more)
The PKHD1 p.Gly448Arg variant was identified in 4 of 618 proband chromosomes (frequency: 0.0065) from individuals with polycystic kidney disease (Eisenberger_2015_PMID:25646624; Bergmann_2005_PMID:15698423; Vora_2017_PMID:28518170; Sharp_2005_PMID:15805161). The variant was identified in dbSNP (ID: rs149781976), LOVD 3.0, ClinVar (classified as uncertain significance by EGL genetics, CeGaT Praxis fuer Humangenetik Tuebingen, Fulgent Genetics and Counsyl for autosomal recessive polycystic kidney disease, and as likely benign by Invitae) and the RWTH AAachen University ARPKD database. The variant was identified in control databases in 445 of 282546 chromosomes at a frequency of 0.001575 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 330 of 128880 chromosomes (freq: 0.002561), Other in 14 of 7220 chromosomes (freq: 0.001939), Latino in 54 of 35432 chromosomes (freq: 0.001524), European (Finnish) in 19 of 25122 chromosomes (freq: 0.000756), South Asian in 16 of 30616 chromosomes (freq: 0.000523), African in 11 of 24968 chromosomes (freq: 0.000441) and Ashkenazi Jewish in 1 of 10358 chromosomes (freq: 0.000097), but was not observed in the East Asian population. The p.Gly448 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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: SCV001876964.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
Sex: female
Geographic origin: Netherlands
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Uncertain significance
(-)
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002034935.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Uncertain significance
(-)
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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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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035961.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely benign
(Sep 25, 2024)
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no assertion criteria provided
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: SCV004738288.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 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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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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An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease. | Eisenberger T | PloS one | 2015 | PMID: 25646624 |
Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. | Sharp AM | Journal of medical genetics | 2005 | PMID: 15805161 |
Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). | Bergmann C | Kidney international | 2005 | PMID: 15698423 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKHD1 | - | - | - | - |
Text-mined citations for rs149781976 ...
HelpRecord 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.