GeneBe

PKHD1

protein-coding

PKHD1 ciliary IPT domain containing fibrocystin/polyductin, the group of IPT domain containing

Gene summary

The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

Previous symbols:
  • TIGM1

MANE transcript

NM_138694.4

Inheritance

AR, AD

ClinVar variants

P:1803U:2082B:1918

Top phenotype

Polycystic kidney disease 4 with or without polycystic liver disease

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr6:51,615,299-52,087,613

External References & Databases

Ensembl (ENSG00000170927)NCBI Gene (5314)OMIM (606702)HGNC:9016GenCCUniProt (P08F94)AlphaFoldClinVar (PKHD1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~472.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

polycystic kidney disease 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033004

Submitter: Labcorp Genetics (formerly Invitae)

nephrocalcinosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0001567

Submitter: PanelApp Australia

nephrocalcinosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0001567

Submitter: PanelApp Australia

polycystic kidney disease 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033004

Submitter: Genomics England PanelApp

polycystic kidney disease 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033004

Submitter: G2P

autosomal recessive polycystic kidney diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009889

Submitter: ClinGen

*PKHD1* was first reported in relation to autosomal recessive polycystic kidney disease in 2002 (Ward et al., PMID: 11919560). Autosomal recessive polycystic kidney disease (ARPKD) is a rare, genetic hepatorenal fibrocystic syndrome characterized by cystic dilatation and ectasia of renal collecting tubules, and a ductal plate malformation of the liver resulting in congenital hepatic fibrosis. Clinical presentation, whilst typically in utero or at birth, is variable and in the most severe cases includes Potter-sequence, oligohydramnios, pulmonary hypoplasia, and massively enlarged echogenic kidneys. Heterozygous carriers of pathogenic variants in *PKHD1* have been associated with susceptibility to liver and/or kidney cysts in two publications (PMID: 21945273, 28375157). However, in reviewing the evidence associating *PKHD1* with monoallelic late-onset polycystic kidney disease, it was unclear if the relationship represents a monogenic disorder with reduced penetrance or a risk factor. Published family studies and long-term phenotypic data are currently limited so, without clear evidence, it was decided to not curate *PKHD1* for a separate monoallelic disorder. Seventeen variants (missense, indel, nonsense, and frameshift) reported in ten probands in two publications (PMIDs: 11919560, 12506140) are included in this biallelic curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by animal models phenocopying the ARPKD liver phenotype, although the kidney disease is milder in rodents than humans, and expression studies including ciliary/basal body localization (PMIDs: 11919560, 12925574, 14983006, 18782757, 15830394, 17519956, 18286309). The pck rat with homozygous *Pkhd1* knockout exhibited significantly less immunoreactivity of the ARPKD protein, fibrocystin (FBC), than wild-type rats. Some collecting duct epithelia completely lacked detectable FPC expression at the cellular level and only ~5% of the pck renal cysts retained FPC labelling with most being at the early stage of cystogenesis with no FPC labelling in large cysts of the pck rat kidneys (PMID:14983006). These findings indicate that significant reduction/loss of *PKHD1* expression is associated with cystogenesis in ARPKD. Similar results were seen in a mouse model designed with a targeting construct disrupting exon 15 and deleting exon 16, which resulted in a variant allele. Mice heterozygous for the allele were intercrossed to produce homozygous *Pkhd1*-/- mice. These mice had cystic or dilated-duct phenotypes in the pancreas with mild-severe tubular dilation (PMID: 18235088, 18782757). In summary, *PKHD1* is definitively associated with autosomal recessive polycystic kidney disease (ARPKD-*PKHD1*). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cystic and Ciliopathy Disorders GCEP on the meeting date 11/11/2020 (SOP Version 8).

polycystic kidney disease 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033004

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

autosomal recessive polycystic kidney diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009889

Submitter: Myriad Women's Health

Caroli diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010913

Submitter: Orphanet

autosomal recessive polycystic kidney diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009889

Submitter: Orphanet

polycystic kidney disease 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033004

Submitter: Natera

Clinical Genomic Database (CGD)

Polycystic kidney disease 4 with or without polycystic liver diseaseAR

Manifestation: Allergy/Immunology/Infectious; Endocrine; Gastrointestinal; Renal

Intervention: Allergy/Immunology/Infectious; Gastrointestinal; Pulmonary; Pharmacogenomic; Renal

Rationale: Initially, neonates may require interventions related to compromises in respiratory and renal function, including surgical interventions and dialysis as necessary (renal transplant may be indicated as well); Surveillance and interventions for complications related to systemic and portal hypertension can be beneficial; Medical treatment (eg, with ACE inhibitors or ARBs) can be beneficial; Other interventions, such as nutritional and endocrinological (eg, GH treatment) support may be beneficial; Prophylaxis against specific infectious agents is indicated; Certain types of medications, such as sympathomimetic or nephrotoxic agents should be avoided or used judiciously if necessary

Refs: 13764315; 4688793; 2702087; 7554350; 11919560; 12506140; 12728091; 15108277; 15706593; 16523049; 21896375; 20301501; 21046169; 22464505; 22882926; 23041322; 23941846; 24114580; 24162162Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PKHD1 variants in ClinVar

36 Conditions Cataloged
Autosomal recessive polycystic kidney diseaseTotal: 4970
Polycystic kidney disease 4Total: 2007
not providedTotal: 1164
PKHD1-related disorderTotal: 908
Inborn genetic diseasesTotal: 474
not specifiedTotal: 361
Polycystic kidney diseaseTotal: 57
Autosomal dominant polycystic liver diseaseTotal: 55

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138694.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
138
clinvar
1739
clinvar
5
clinvar
 1884
missense
18
clinvar
258
clinvar
1926
clinvar
162
clinvar
12
clinvar
 2376
nonsense
137
clinvar
267
clinvar
7
clinvar
 411
start loss
1
clinvar
2
clinvar
 3
frameshift
266
clinvar
566
clinvar
6
clinvar
 838
splice donor/acceptor (+/-2bp)
30
clinvar
256
clinvar
5
clinvar
 291
Total452135120821901175803

Highest pathogenic variant AF is 0.00056590105

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_138694.4RefSeqNP_619639.366MANE Select
ENST00000371117.8EnsemblENSP00000360158.366MANE Select
NM_170724.3RefSeqNP_733842.260Standard
ENST00000340994.4EnsemblENSP00000341097.460Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • kidney development
  • cellular calcium ion homeostasis
  • positive regulation of cell population proliferation
  • regulation of centrosome duplication
  • regulation of TOR signaling

Molecular Function

  • protein binding
  • signaling receptor activity

Cellular Component

  • chromosome, centromeric region
  • cytoplasm
  • centrosome
  • cilium
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000371117
Coding exons
66
Length
472326
Individuals with no LoFs
125106
Homozygous LoFs
0
Heterozygous LoFs
642
Defined
125748
p
0.00256
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.98222452.12e+31.060.00011526495
Missense (PolyPhen)560588.920.950897885
Synonymous-0.5608298091.030.00004628254
Loss of Function5.281071840.5800.000009922196

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00190.0018notable
Latino/Admixed American0.00260.0026notable
Ashkenazi Jewish0.00750.0075notable
East Asian0.00100.0010notable
Finnish0.00720.0072notable
European (Non-Finnish)0.00190.0018notable
South Asian0.00170.0017notable
Other0.00230.0023notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May be required for correct bipolar cell division through the regulation of centrosome duplication and mitotic spindle assembly. May be a receptor protein that acts in collecting-duct and biliary differentiation. {ECO:0000269|PubMed:20554582}.;
Disease
DISEASE: Note=Loss-of-function PKHD1 variations may cause autosomal dominant polycystic liver disease (PCLD) in patients that lack variations in known causative genes, such as PRKCSH and SEC63. {ECO:0000269|PubMed:28375157}.;

Recessive Scores

pRec
0.255

Intolerance Scores

LoFtool
0.00772
RVIS EVS
0.38
RVIS percentile EVS
75.51

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.0854

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerHighMediumHigh
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