PRKCSH

protein-coding

protein kinase C substrate 80K-H, the group of MRH domain containing |EF-hand domain containing

Gene summary

This gene encodes the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum. The encoded protein is an acidic phosphoprotein known to be a substrate for protein kinase C. Mutations in this gene have been associated with the autosomal dominant polycystic liver disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Previous symbols:

G19P1
PCLD
PLD1

MANE transcript

NM_001289104.2

Inheritance

ClinVar variants

P:51U:186B:141

Top phenotype

Polycystic liver disease 1 with or without kidney cysts

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr19:11,435,284-11,450,968

External References & Databases

Ensembl (ENSG00000130175)

Transcript & Mutation Effects

hg38 • Region Span ~15.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

polycystic liver disease 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008265

Submitter: Orphanet

polycystic liver disease 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008265

Submitter: Labcorp Genetics (formerly Invitae)

polycystic liver disease 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008265

Submitter: Ambry Genetics

polycystic liver disease 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008265

Submitter: ClinGen

PRKCSH was FIRST reported in relation to autosomal dominant polycystic liver disease in 2003 (Li et al., PMID 12529853). Autosomal dominant polycystic liver disease due to PRKCSH mutations (ADPLD-PRKCSH) is diagnosed in adults with a family history of liver cysts, under age 40 with any number of liver cysts and individuals over the age of 40 with four or more liver cysts. Kidney cysts are present in approximately 28-35% of cases with absent to mild kidney disease and no association with progression to end stage renal disease (PMID 12529853, PMID 15057895, PMID 29038287). At least nine unique variants (e.g. nonsense, frameshift, splice site, missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data , population data and experimental data. Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least nine probands and in at least 5 publications (PMID 12529853, PMID 12577059, PMID 15057895, PMID 20095989, PMID 28375157). Variants in this gene segregated with disease in at least 109 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is heterozygous loss of function (PMID 12529853) with a secondary somatic hit resulting in loss of heterozygosity suggested (PMID 21856269). This gene-disease association is supported by expression studies in cell models, patient derived samples, and mouse models. In summary, PRKCSH is definitively associated with AUTOSOMAL DOMINANT POLYCYSTIC LIVER DISEASE. 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 July 8th 2020 (SOP Version 7).

polycystic liver disease 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008265

Submitter: Genomics England PanelApp

polycystic liver disease 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008265

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Polycystic liver disease 1 with or without kidney cystsAD

Manifestation: Gastrointestinal; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Though some individuals may require treatment, it is unclear if early (genetic) diagnosis would be beneficial; Liver transplantion has been described

Refs: 11047756; 12577059; 12529853; 16835903; 20095989; 22415584

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRKCSH variants in ClinVar

10 Conditions Cataloged

not providedTotal: 325

Polycystic liver disease 1Total: 178

Inborn genetic diseasesTotal: 101

not specifiedTotal: 62

PRKCSH-related disorderTotal: 25

Autosomal dominant polycystic liver diseaseTotal: 14

Primary ciliary dyskinesia 30Total: 2

ODAD3-related disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001289104.2. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			11 clinvar	88 clinvar	3 clinvar	102
missense		3 clinvar	161 clinvar	50 clinvar		214
nonsense	9 clinvar	6 clinvar				15
start loss						0
frameshift	11 clinvar	8 clinvar	1 clinvar			20
splice donor/acceptor (+/-2bp)	5 clinvar	9 clinvar	13 clinvar			27
Total	25	26	186	138	3	378

Highest pathogenic variant AF is 0.00011970893

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 71 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001289104.2	RefSeq	NP_001276033.1	16	MANE Select
ENST00000677123.1	Ensembl	ENSP00000503163.1	16	MANE Select
NM_001001329.3	RefSeq	NP_001001329.1	16	Standard
NM_001289102.2	RefSeq	NP_001276031.1	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
prkcsh	Danio rerio	Structure: post-vent region Quality: kinked abnormal

Gene / Model

Organism

Observed Phenotype

prkcsh

Danio rerio

Structure: post-vent region

Quality: kinked

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
Post-translational protein phosphorylation
Calnexin/calreticulin cycle
Post-translational protein modification
Metabolism of proteins

Biological Process

N-glycan processing
intracellular signal transduction
post-translational protein modification
cellular protein metabolic process

Molecular Function

protein kinase C binding
calcium ion binding
protein binding
ion channel binding
phosphoprotein binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum lumen
glucosidase II complex
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252455
Coding exons: 16
Length: 15675
Individuals with no LoFs: 125701
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125748
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.532	286	312	0.915	0.0000213	3448
Missense (PolyPhen)		91	116.17	0.78336		1278
Synonymous	-2.64	178	138	1.29	0.0000114	964
Loss of Function	2.64	17	33.5	0.508	0.00000169	389

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00075	0.00074	rare
European (Non-Finnish)	0.00015	0.00014	rare
South Asian	0.00020	0.00020	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulatory subunit of glucosidase II that cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins (PubMed:10929008). Required for efficient PKD1/Polycystin-1 biogenesis and trafficking to the plasma membrane of the primary cilia (By similarity). {ECO:0000250|UniProtKB:O08795, ECO:0000269|PubMed:10929008}.;
Disease: DISEASE: Polycystic liver disease 1 with or without kidney cysts (PCLD1) [MIM:174050]: An autosomal dominant hepatobiliary disease characterized by overgrowth of biliary epithelium and supportive connective tissue, resulting in multiple liver cysts. A subset of patients may develop kidney cysts that usually do not result in clinically significant renal disease. {ECO:0000269|PubMed:12529853, ECO:0000269|PubMed:12577059, ECO:0000269|PubMed:28375157}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.138

Intolerance Scores

LoFtool: 0.445
RVIS EVS: -0.89
RVIS percentile EVS: 10.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.927

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High