PLCZ1

protein-coding

phospholipase C zeta 1, the group of EF-hand domain containing|Phospholipases|C2 domain containing phospholipases

Gene summary

The protein encoded by this gene is a member of the phosphoinositide-specific phospholipase C family. Members in this family, classified into six isotypes that are tissue- and organ-specific, hydrolyze phosphatidylinositol 4,5-bisphosphate just before the phosphate group to yield diacylglycerol and inositol 1,4,5-trisphosphate. This protein localizes to the acrosome in spermatozoa and elicits Ca(2+) oscillations and egg activation during fertilization that leads to early embryonic development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

MANE transcript

NM_033123.4

Inheritance

ClinVar variants

P:15U:68B:10

Top phenotype

Spermatogenic failure 17

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr12:18,683,169-18,738,100

External References & Databases

Ensembl (ENSG00000139151)

Transcript & Mutation Effects

hg38 • Region Span ~54.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spermatogenic failure 17DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014970

Submitter: ClinGen

*PLCZ1* was first reported in relation to male infertility due to fertilization failure in 2009 (Heytons *et al.*, PMID: 19584136). Note, this disease concept is currently represented by the term “spermatogenic failure 17”. However, the new term (male infertility due to fertilization failure) has been requested by the Male Infertility GCEP because the primary mechanism associated with *PLCZ1* variants is impaired oocyte activation, resulting in fertilization failure. In the original paper, an autosomal dominant mode of inheritance was originally proposed as only a single heterozygous variant was identified in the patient. However, later Kashir et al. found a second variant in trans reported in the same patient, confirming an autosomal recessive inheritance pattern. Eleven variants (five loss-of-function and six missense) that have been reported in six probands in four publications (PMIDs: 36529831, 32048714, 31953539, 22095789) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. The underlying mechanistic effect is that an absent or impaired *PLCZ1* does not induce calcium release from the ER within the oocyte (PMID:12117804, 12416999). Thus, oocyte activation, fertilization and embryonic development fail. This gene-disease relationship is also supported by experimental evidence (e.g. animal models, expression studies, in vivo functional assays, and biochemical function) (PMIDs: 29358633, 12416999, 12117804, 32923619, 35863052). In summary, there is definitive evidence supporting the relationship between *PLCZ1* and autosomal recessive male infertility due to fertilization failure. 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 Male Infertility GCEP on the meeting date May 20, 2026 (SOP Version 12).

spermatogenic failure 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014970

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spermatogenic failure 17AR

Manifestation: Genitourinary

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

Refs: 26721930

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLCZ1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 73

Spermatogenic failure 17Total: 17

not providedTotal: 9

PLCZ1-related disorderTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033123.4. 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				5 clinvar		5
missense	4 clinvar	2 clinvar	66 clinvar	4 clinvar	1 clinvar	77
nonsense	1 clinvar	3 clinvar	1 clinvar			5
start loss						0
frameshift	2 clinvar	1 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar				2
Total	8	7	68	9	1	93

Highest pathogenic variant AF is 0.00013702553

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033123.4	RefSeq	NP_149114.2	14	MANE Select
ENST00000266505.12	Ensembl	ENSP00000266505.7	14	MANE Select
NM_001330769.1	RefSeq	NP_001317698.1	11	Standard
NM_001330774.2	RefSeq	NP_001317703.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inositol phosphate metabolism - Homo sapiens (human)
Oocyte meiosis - Homo sapiens (human)
Thyroid hormone signaling pathway - Homo sapiens (human)
Calcium signaling pathway - Homo sapiens (human)
Phosphatidylinositol signaling system - Homo sapiens (human)

Biological Process

calcium ion transport
positive regulation of cytosolic calcium ion concentration
multicellular organism development
egg activation
lipid catabolic process

Molecular Function

phosphatidylinositol phospholipase C activity
calcium ion binding
phosphatidylinositol-4,5-bisphosphate binding
phosphatidylinositol-5-phosphate binding
phosphatidylinositol-3-phosphate binding

Cellular Component

nucleus
nucleoplasm
nucleolus
cytosol
pronucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000266505
Coding exons: 14
Length: 54889
Individuals with no LoFs: 125646
Homozygous LoFs: 0
Heterozygous LoFs: 93
Defined: 125739
p: 0.000370

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.608	342	312	1.10	0.0000153	4017
Missense (PolyPhen)		121	120.16	1.007		1634
Synonymous	-0.756	112	102	1.10	0.00000482	1076
Loss of Function	1.44	23	31.8	0.723	0.00000157	417

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00060	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00053	0.00052	rare
South Asian	0.00023	0.00023	rare
Other	0.00049	0.00049	rare

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. In vitro, hydrolyzes PtdIns(4,5)P2 in a Ca(2+)- dependent manner. Triggers intracellular Ca(2+) oscillations in oocytes solely during M phase and is involved in inducing oocyte activation and initiating embryonic development up to the blastocyst stage. Is therefore a strong candidate for the egg- activating soluble sperm factor that is transferred from the sperm into the egg cytoplasm following gamete membrane fusion. May exert an inhibitory effect on phospholipase-C-coupled processes that depend on calcium ions and protein kinase C, including CFTR trafficking and function. {ECO:0000250|UniProtKB:Q8K4D7, ECO:0000269|PubMed:12416999, ECO:0000269|PubMed:14697805, ECO:0000269|PubMed:15579586, ECO:0000269|PubMed:26721930, ECO:0000305}.;
Disease: DISEASE: Spermatogenic failure 17 (SPGF17) [MIM:617214]: An autosomal recessive infertility disorder due to failure of oocyte activation and fertilization by sperm that otherwise exhibits normal morphology. {ECO:0000269|PubMed:26721930}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0925

Intolerance Scores

LoFtool: 0.949
RVIS EVS: -0.47
RVIS percentile EVS: 23.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.135

Gene Damage Prediction

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