PLD1

protein-coding

phospholipase D1, the group of Phospholipases|Pleckstrin homology domain containing

Gene summary

This gene encodes a phosphatidylcholine-specific phospholipase which catalyzes the hydrolysis of phosphatidylcholine in order to yield phosphatidic acid and choline. The enzyme may play a role in signal transduction and subcellular trafficking. Alternative splicing results in multiple transcript variants with both catalytic and regulatory properties. [provided by RefSeq, Sep 2011]

MANE transcript

NM_002662.5

Inheritance

ClinVar variants

P:42U:204B:64

Top phenotype

Cardiac valvular dysplasia 1

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr3:171,600,404-171,810,950

External References & Databases

Ensembl (ENSG00000075651)

Transcript & Mutation Effects

hg38 • Region Span ~210.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiac valvular defect, developmentalDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008913

Submitter: G2P

cardiac valvular defect, developmentalSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008913

Submitter: Labcorp Genetics (formerly Invitae)

PLD1-related congenital heart diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1010144

Submitter: ClinGen

*PLD1* was first reported in relation to autosomal recessive *PLD1*-related congenital heart disease in 2017 (Ta-Shma et al., PMID: 27799408). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Cardiac valvular dysplasia 1 and congenital heart disease. Nineteen unique variants (missense, nonsense, frameshift, splicing) that have been reported in twelve probands in three publications (PMIDs: 27799408, 33645542, 38171566) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached (PMIDs: 37770978, 36923242). This gene-disease relationship is also supported by a knockout mouse model, expression data in chick embryo, and functional alteration data (PMIDs: 27799408, 33645542). In summary, *PLD1* is definitively associated with autosomal recessive *PLD1*-related congenital heart 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 Congenital Heart Disease GCEP on the meeting date December 2nd, 2024 (SOP Version 11).

cardiac valvular defect, developmentalMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008913

Submitter: Ambry Genetics

cardiac valvular defect, developmentalSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008913

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cardiac valvular dysplasia 1AR

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Individuals may manifest with cardiac valvular disease, and awareness may allow early diagnosis and medical or surgical management

Refs: 27799408

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLD1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 196

Inborn genetic diseasesTotal: 139

Cardiac valvular defect, developmentalTotal: 44

PLD1-related disorderTotal: 32

not specifiedTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002662.5. 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				32 clinvar	6 clinvar	38
missense	1 clinvar	6 clinvar	195 clinvar	19 clinvar	7 clinvar	228
nonsense	5 clinvar	7 clinvar	2 clinvar			14
start loss						0
frameshift	5 clinvar	6 clinvar				11
splice donor/acceptor (+/-2bp)	4 clinvar	8 clinvar	7 clinvar			19
Total	15	27	204	51	13	310

Highest pathogenic variant AF is 0.00027938478

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002662.5	RefSeq	NP_002653.1	26	MANE Select
ENST00000351298.9	Ensembl	ENSP00000342793.4	26	MANE Select
NM_001130081.3	RefSeq	NP_001123553.1	25	Standard
ENST00000356327.10	Ensembl	ENSP00000348681.5	25	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pld1b	Danio rerio	Structure: whole organism Quality: curved abnormal

Gene / Model

Organism

Observed Phenotype

pld1b

Danio rerio

Structure: whole organism

Quality: curved

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fc gamma R-mediated phagocytosis - Homo sapiens (human)
Ether lipid metabolism - Homo sapiens (human)
Glycerophospholipid metabolism - Homo sapiens (human)
Choline metabolism in cancer - Homo sapiens (human)
Glutamatergic synapse - Homo sapiens (human)

Biological Process

phosphatidic acid biosynthetic process
chemotaxis
small GTPase mediated signal transduction
Ras protein signal transduction
lipid catabolic process

Molecular Function

phospholipase D activity
protein binding
phosphatidylinositol binding
N-acylphosphatidylethanolamine-specific phospholipase D activity

Cellular Component

Golgi membrane
lysosomal membrane
endosome
endoplasmic reticulum membrane
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000351298
Coding exons: 26
Length: 210546
Individuals with no LoFs: 125578
Homozygous LoFs: 0
Heterozygous LoFs: 170
Defined: 125748
p: 0.000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.184	602	615	0.979	0.0000341	7120
Missense (PolyPhen)		224	237.25	0.94417		2763
Synonymous	0.957	200	218	0.918	0.0000128	1956
Loss of Function	2.36	42	62.0	0.677	0.00000327	737

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00090	0.00090	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00093	0.00092	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00091	0.00090	rare
South Asian	0.00048	0.00036	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. May be involved in the regulation of perinuclear intravesicular membrane traffic (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.226

Intolerance Scores

LoFtool: 0.977
RVIS EVS: -0.01
RVIS percentile EVS: 52.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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