ClinVar Genomic variation as it relates to human health
NM_138694.4(PKHD1):c.334G>A (p.Gly112Arg)
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(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_138694.4(PKHD1):c.334G>A (p.Gly112Arg)
Variation ID: 499278 Accession: VCV000499278.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p12.2 6: 52079956 (GRCh38) [ NCBI UCSC ] 6: 51944754 (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 Feb 20, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138694.4:c.334G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619639.3:p.Gly112Arg missense NM_170724.3:c.334G>A NP_733842.2:p.Gly112Arg missense NC_000006.12:g.52079956C>T NC_000006.11:g.51944754C>T NG_008753.1:g.12670G>A - Protein change
- G112R
- Other names
- -
- Canonical SPDI
- NC_000006.12:52079955:C:T
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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.
Exome Aggregation Consortium (ExAC) 0.00034
The Genome Aggregation Database (gnomAD), exomes 0.00034
The Genome Aggregation Database (gnomAD) 0.00039
Trans-Omics for Precision Medicine (TOPMed) 0.00041
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 5, 2022 | RCV000595963.8 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 27, 2024 | RCV000671191.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 11, 2021 | RCV001290597.2 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001292159.2 | |
Uncertain significance (1) |
no assertion criteria provided
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Sep 1, 2021 | RCV001844839.2 |
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
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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
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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
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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 07, 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: SCV000796143.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Dec 20, 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: SCV000704700.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
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: SCV000897305.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Jan 11, 2021)
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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: SCV001478686.1
First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021 |
Comment:
Variant summary: PKHD1 c.334G>A (p.Gly112Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: PKHD1 c.334G>A (p.Gly112Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 251404 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00034 vs 0.0071), allowing no conclusion about variant significance. c.334G>A has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Bergmann_2005, Eisenberger_2015, Dafinger_2020). These reports 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 05, 2022)
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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: SCV002568644.2
First in ClinVar: Sep 03, 2022 Last updated: Mar 04, 2023 |
Comment:
Reported with additional PKHD1 variants (phase unknown) in a patient with polycystic kidney disease in published literature (Bergmann et al., 2005); In silico analysis supports … (more)
Reported with additional PKHD1 variants (phase unknown) in a patient with polycystic kidney disease in published literature (Bergmann et al., 2005); 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: 25525159, 25646624, 33112055, 15698423) (less)
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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: SCV001413842.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Polycystic Kidney disease
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: SCV001480760.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Comment:
The PKHD1 p.Gly112Arg variant was identified in 1 of 328 proband chromosomes (frequency: 0.003) from individuals or families with autosomal-recessive polycystic kidney disease (ARPKD; Bergmann … (more)
The PKHD1 p.Gly112Arg variant was identified in 1 of 328 proband chromosomes (frequency: 0.003) from individuals or families with autosomal-recessive polycystic kidney disease (ARPKD; Bergmann 2005). The variant was also identified in dbSNP (ID: rs149841071) as N/A, LOVD 3.0, RWTH AAachen University ARPKD database (classified as pathogenic). The variant was not identified in ClinVar or GeneInsight-COGR databases. The variant was identified in control databases in 95 of 277140 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Gly112 residue is not 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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: SCV001876984.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
Sex: female
Geographic origin: Netherlands
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Uncertain significance
(May 22, 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: SCV002083415.1
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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The carboxy-terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC-activation. | Dafinger C | Journal of cellular and molecular medicine | 2020 | PMID: 33112055 |
An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease. | Eisenberger T | PloS one | 2015 | PMID: 25646624 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 rs149841071 ...
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.