PLA2G6

protein-coding

phospholipase A2 group VI, the group of Phospholipases|Ankyrin repeat domain containing|Patatin like phospholipase domain containing

Gene summary

The protein encoded by this gene is an A2 phospholipase, a class of enzyme that catalyzes the release of fatty acids from phospholipids. The encoded protein may play a role in phospholipid remodelling, arachidonic acid release, leukotriene and prostaglandin synthesis, fas-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells. Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only three of them have been determined to date. [provided by RefSeq, Dec 2010]

MANE transcript

NM_003560.4

Inheritance

ClinVar variants

P:235U:346B:309

Top phenotype

Parkinson disease 14, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr22:38,111,495-38,214,778

External References & Databases

Ensembl (ENSG00000184381)

Transcript & Mutation Effects

hg38 • Region Span ~103.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodegeneration with brain iron accumulation 2BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012444

Submitter: Genomics England PanelApp

PLA2G6-associated neurodegenerationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017998

Submitter: ClinGen

*PLA2G6*, the gene encoding phospholipase A2 group VI, was first reported in relation to autosomal recessive *PLA2G6*-associated neurodegeneration (PLAN) in 2006 (Morgan et al., PMID: 16783378). PLAN is a continuum of three phenotypes with overlapping clinical and radiological features: (1) infantile neuronal dystrophy (INAD) or NBIA2A (OMIM: 256600), (2) atypical neuronal dystrophy (ANAD) with childhood-onset or NBIA2B (OMIM: 610217), (3) adult-onset dystonia-parkinsonism form named PARK14 (OMIM: 612953), to possibly a certain subtype of hereditary spastic paraplegia (HSP) (Deng et al. 2023. PMID: 37236368). INAD, or NBIA2A, usually begins between ages six months and three years with rapid progression, characterized by psychomotor regression or delay, hypotonia, progressive spastic tetraparesis, and visual impairment. Many affected children do not survive beyond their first decade. ANAD, or NBIA2B, shows more phenotypic variability than INAD and may present in early childhood but can be as late as the end of the second decade. The presenting signs may be speech delay, gait instability, ataxia, postural instability, dystonia, spasticity, and cognitive decline with autistic features. Strabismus, nystagmus, and optic atrophy are common. PARK14, or *PLA2G6*-related dystonia-parkinsonism, has a variable age of onset, but most individuals present gait disturbance or neuropsychiatric changes and develop dystonia and parkinsonism (bradykinesia, resting tremor, rigidity, and postural instability) in their late teens to early twenties. Cerebellar atrophy is a typical radiological sign which correlates with the severity of the phenotype. Another common feature, iron accumulation within the globus pallidum and substantia nigra are variable and does not correlate with the severity of the phenotype (Gregory et al. GeneReviews, PMID: 20301718, https://www.ncbi.nlm.nih.gov/books/NBK1675/). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern AND pathological phenotypes. Therefore, the following disease entities have been lumped into one disease entity: NBIA2A (OMIM: 256600), NBIA2B (OMIM: 610217), autosomal recessive Parkinson disease 14 (OMIM: 612953), to possibly a certain subtype of hereditary spastic paraplegia (HSP). To date, 217 pathogenic or likely pathogenic variants in *PLA2G6* (OMIM: 603604) including missense or nonsense variants, splicing variants, small insertions/deletions, multi-exon deletion, and copy number variations have been submitted to ClinVar. This curation includes 13 variants from 10 probands in one publication (Morgan et al. 2006. PMID: 16783378). These variants (missense, in-frame indel, nonsense, frameshift) have also been reported in other probands in 26 publications (PMIDs: 28097321, 18799783, 22934738, 19138334, 29859652, 20619503, 29395073, 18359254, 24745848, 33101984, 32860008, 20886109, 25164370, 29482223, 24108619, 20619503, 29915382, 30772976, 34622992, 31548400, 28097321, 17033970, 24628589, 28714225, 34272103, 27196560). More evidence is available in the literature, but the maximum score for genetic evidence (12 points.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence. This includes the biochemical function of the gene product, which is consistent with the features observed in human patients. *PLA2G6* encodes a calcium-independent group VI phospholipase A2, iPLA2β, which localizes to the neuronal mitochondria and endosomal and lysosomal membranes. In the nervous system, iPLA2β may be involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α-synuclein aggregation (Zhou et al. 2016. PMID: 26755131; Malley et al. 2018. PMID: 29472584; Deng et al, 2023, PMID: 37236368). In addition, non-human animal models Knock out mice, Drosophila) recapitulate the clinical and histopathological features of the disease (Malik et al. 2008. PMID: 18202189; Beck et al. 2008. PMID: 21813701; Zhao et al. 2011. PMID: 22046428) and a *Drosophila *model (Lin et al. 2018. PMID: 29909971) (Experimental evidence – 6 points). In summary, there is definitive evidence supporting the relationship between *PLA2G6* and *PLA2G6*-associated neurodegeneration (PLAN), an autosomal recessive disorder. 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 Lysosomal Diseases Gene Curation Expert Panel on March 21, 2024 (SOP v10).

neurodegeneration with brain iron accumulation 2ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024457

Submitter: Ambry Genetics

neurodegeneration with brain iron accumulation 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024457

Submitter: Genomics England PanelApp

autosomal recessive Parkinson disease 14MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013060

Submitter: Ambry Genetics

neurodegeneration with brain iron accumulation 2ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024457

Submitter: G2P

neurodegeneration with brain iron accumulation 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024457

Submitter: Labcorp Genetics (formerly Invitae)

neurodegeneration with brain iron accumulation 2BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012444

Submitter: Ambry Genetics

autosomal recessive Parkinson disease 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013060

Submitter: Genomics England PanelApp

neurodegeneration with brain iron accumulation 2ASUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024457

Submitter: Orphanet

autosomal recessive Parkinson disease 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013060

Submitter: Labcorp Genetics (formerly Invitae)

neurodegeneration with brain iron accumulation 2BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012444

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive Parkinson disease 14SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013060

Submitter: Orphanet

Clinical Genomic Database (CGD)

Parkinson disease 14, autosomal recessiveAR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: In Parkinson disease 14, response to levodopa has been documented

Comments: Some individuals with Neurodegeneration with brain iron accumulation have been described as having Karak syndrome

Refs: 17033970; 16783378; 18443314; 18981035; 18570303; 20584031; 20886109; 20938027; 21520282; 21700586; 21812034; 22934738

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLA2G6 variants in ClinVar

29 Conditions Cataloged

Infantile neuroaxonal dystrophyTotal: 886

not providedTotal: 354

PLA2G6-associated neurodegenerationTotal: 141

Neurodegeneration with brain iron accumulation 2BTotal: 119

Autosomal recessive Parkinson disease 14Total: 98

Inborn genetic diseasesTotal: 95

not specifiedTotal: 85

Iron accumulation in brainTotal: 55

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003560.4. 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		1 clinvar	6 clinvar	287 clinvar	3 clinvar	297
missense	11 clinvar	107 clinvar	335 clinvar	17 clinvar	2 clinvar	472
nonsense	22 clinvar	8 clinvar	1 clinvar			31
start loss	1 clinvar	1 clinvar				2
frameshift	30 clinvar	22 clinvar	1 clinvar			53
splice donor/acceptor (+/-2bp)	9 clinvar	23 clinvar	3 clinvar			35
Total	73	162	346	304	5	890

Highest pathogenic variant AF is 0.0002903541

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 70 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003560.4	RefSeq	NP_003551.2	16	MANE Select
ENST00000332509.8	Ensembl	ENSP00000333142.3	16	MANE Select
NM_001004426.3	RefSeq	NP_001004426.1	15	Standard
NM_001199562.3	RefSeq	NP_001186491.1	15	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)
Fc gamma R-mediated phagocytosis - Homo sapiens (human)
Ether lipid metabolism - Homo sapiens (human)
Glycerophospholipid metabolism - Homo sapiens (human)
Vascular smooth muscle contraction - Homo sapiens (human)

Biological Process

positive regulation of protein phosphorylation
chemotaxis
positive regulation of cytosolic calcium ion concentration
memory
urinary bladder smooth muscle contraction

Molecular Function

phospholipase A2 activity
calmodulin binding
hydrolase activity
serine hydrolase activity
protein kinase binding

Cellular Component

extracellular space
mitochondrion
microtubule organizing center
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000332509
Coding exons: 16
Length: 94196
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 63
Defined: 125747
p: 0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.21	425	502	0.847	0.0000350	5244
Missense (PolyPhen)		134	170.61	0.78542		1755
Synonymous	1.83	181	215	0.841	0.0000158	1639
Loss of Function	2.20	21	35.1	0.598	0.00000201	379

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00029	0.00029	rare
South Asian	0.00016	0.00016	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the release of fatty acids from phospholipids. It has been implicated in normal phospholipid remodeling, nitric oxide-induced or vasopressin-induced arachidonic acid release and in leukotriene and prostaglandin production. May participate in fas mediated apoptosis and in regulating transmembrane ion flux in glucose-stimulated B-cells. Has a role in cardiolipin (CL) deacylation. Required for both speed and directionality of monocyte MCP1/CCL2-induced chemotaxis through regulation of F- actin polymerization at the pseudopods.;
Disease: DISEASE: Neurodegeneration with brain iron accumulation 2A (NBIA2A) [MIM:256600]: A neurodegenerative disease characterized by pathologic axonal swelling and spheroid bodies in the central nervous system. Onset is within the first 2 years of life with death by age 10 years. {ECO:0000269|PubMed:16783378, ECO:0000269|PubMed:17033970, ECO:0000269|PubMed:23749988}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Parkinson disease 14 (PARK14) [MIM:612953]: An adult- onset progressive neurodegenerative disorder characterized by parkinsonism, dystonia, severe cognitive decline, cerebral and cerebellar atrophy and absent iron in the basal ganglia on magnetic resonance imaging. {ECO:0000269|PubMed:18570303}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.176

Intolerance Scores

LoFtool: 0.843
RVIS EVS: -1.59
RVIS percentile EVS: 3.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.853

Gene Damage Prediction

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