PLCB1

protein-coding

phospholipase C beta 1, the group of C2 domain containing phospholipases|Phospholipases

Gene summary

The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals. This gene is activated by two G-protein alpha subunits, alpha-q and alpha-11. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_015192.4

Inheritance

AD, AR

ClinVar variants

P:29U:425B:313

Top phenotype

Developmental and epileptic encephalopathy 12

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr20:8,077,251-8,968,360

External References & Databases

Ensembl (ENSG00000182621)

Transcript & Mutation Effects

hg38 • Region Span ~891.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

malignant migrating partial seizures of infancySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017385

Submitter: Orphanet

developmental and epileptic encephalopathy, 12MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013389

Submitter: Ambry Genetics

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

**Note: In September 2021, the ClinGen Epilepsy GCEP opted to change the disease term on this curation from early infantile epileptic encephalopathy, 12 to developmental epileptic encephalopathy. The evidence summary below reflects this change. The original evidence and conclusion remains the same; therefore, the original date of approval has not been changed. ** Pathogenic variants in the PLCB1 gene have been reported in the literature in several individuals with developmental and epileptic encephalopathy, usually characterized by refractory infantile onset seizures, EEG abnormalities- often with hypsarrhythmia, neurologic and developmental regression and long term cognitive and motor impairment. Homozygous or compound heterozygous loss of function variants have been primarily reported in association with this phenotype supporting an autosomal recessive inheritance pattern. Sequence variants (PMIDs: 24684524, 30554916, 31054490, 31883110) as well as large multi-exon deletions (PMID:26818157, 31883110) have been reported in the literature, often from individuals with consanguineous family history. Of note, a recurrent deletion which encompasses the promoter and exons 1-3 of the gene has been reported in multiple individuals (approximate reported breakpoints GRCh37 20:803442-8099252 to 8520654-8575520) (PMIDs:20833646, 22690784, 24684524). Evidence supporting this gene disease pair includes experimental data as well. Supporting experimental data has been reported in a knockout mouse model (PMID:9305844) that exhibited no phenotype in the heterozygous state, but demonstrated delayed growth, low viability and recurrent tonic-clonic seizures in the homozygous state. In summary PLCB1 is definitively associated with autosomal recessive developmental and epileptic encephalopathy. This has been demonstrated in both the clinical and research settings and this evidence has been maintained over time.

developmental and epileptic encephalopathy, 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013389

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013389

Submitter: G2P

developmental and epileptic encephalopathy, 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013389

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 12AR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Individuals may manifest with seizures, and specific knowledge of the underlying cause can help direct selection of optimal therapies for management based on the genetic etiology

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 20833646; 22690784; 28331464

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLCB1 variants in ClinVar

9 Conditions Cataloged

Developmental and epileptic encephalopathy, 12Total: 889

not providedTotal: 219

Inborn genetic diseasesTotal: 182

not specifiedTotal: 71

PLCB1-related disorderTotal: 25

Self-limited epilepsy with centrotemporal spikesTotal: 1

Abnormal brain morphologyTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015192.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	293 clinvar	1 clinvar	303
missense	1 clinvar	1 clinvar	410 clinvar	17 clinvar	2 clinvar	431
nonsense	4 clinvar	3 clinvar				7
start loss						0
frameshift	7 clinvar	2 clinvar	2 clinvar			11
splice donor/acceptor (+/-2bp)	1 clinvar	10 clinvar	4 clinvar			15
Total	13	16	425	310	3	767

Highest pathogenic variant AF is 0.000006576957

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015192.4	RefSeq	NP_056007.1	32	MANE Select
ENST00000338037.11	Ensembl	ENSP00000338185.6	32	MANE Select
NM_182734.3	RefSeq	NP_877398.1	32	Standard
ENST00000378637.6	Ensembl	ENSP00000367904.2	32	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
Platelet activation - Homo sapiens (human)
Cortisol synthesis and secretion - Homo sapiens (human)
Relaxin signaling pathway - Homo sapiens (human)
Aldosterone synthesis and secretion - Homo sapiens (human)

Biological Process

G2/M transition of mitotic cell cycle
signal transduction
G protein-coupled receptor signaling pathway
G protein-coupled acetylcholine receptor signaling pathway
glutamate receptor signaling pathway

Molecular Function

phosphatidylinositol phospholipase C activity
phospholipase C activity
GTPase activator activity
calcium ion binding
protein binding

Cellular Component

nuclear chromatin
nucleus
cytoplasm
cytosol
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338037
Coding exons: 32
Length: 836180
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125748
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.83	381	658	0.579	0.0000350	8034
Missense (PolyPhen)		50	165.45	0.30221		2020
Synonymous	-1.21	259	235	1.10	0.0000132	2185
Loss of Function	6.30	13	69.8	0.186	0.00000356	895

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 12 (EIEE12) [MIM:613722]: A form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high- voltage bursts alternating with almost flat suppression phases. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. {ECO:0000269|PubMed:20833646}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.190

Intolerance Scores

LoFtool: 0.581
RVIS EVS: -0.84
RVIS percentile EVS: 11.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.804

Gene Damage Prediction

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