PNPLA2

protein-coding

patatin like phospholipase domain containing 2, the group of Patatin like phospholipase domain containing|Lipases

Gene summary

This gene encodes an enzyme which catalyzes the first step in the hydrolysis of triglycerides in adipose tissue. Mutations in this gene are associated with neutral lipid storage disease with myopathy. [provided by RefSeq, Jul 2010]

MANE transcript

NM_020376.4

Inheritance

ClinVar variants

P:46U:281B:204

Top phenotype

Neutral lipid storage disease with myopathy

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr11:818,914-825,573

External References & Databases

Ensembl (ENSG00000177666)

Transcript & Mutation Effects

hg38 • Region Span ~6.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neutral lipid storage myopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012545

Submitter: Orphanet

neutral lipid storage myopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012545

Submitter: ClinGen

The relationship between the PNPLA2 gene and neutral lipid storage disease with myopathy (NLSDM), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 9, 2022. PNPLA2 encodes patatin-like phospholipase domain-containing protein (aka adipose triglyceride lipase), an enzyme involved in triglyceride hydrolysis in adipocytes and in non-adipocyte droplets (PMID: 15550674) via catalyzing the hydrolysis of long-chain fatty acid esters at the sn2 position of the glycerol backbone. Among individuals with NLSDM, PNPLA2 deficiency leads to accumulation of incompletely degraded triglycerides in leukocytes and skeletal and cardiac muscle cells, resulting in the characteristic disease manifestations of myopathy and cardiomyopathy (PMID: 17187067, PMID: 21544567). The disease mechanism of NLSDM is loss of function. NLSDM was first reported in 2007 (PMID: 17187067), and this publication was the first report of biallelic variants in PNPLA2 among patients with NLSDM. Both case-level (genetic) and experimental evidence support the relationship between PNPLA2 and NLSDM. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 17187067, PMID: 21544567, PMID: 25956450, PMID: 24332944, PMID: 22832386). In total, 10 variants from eight probands in five publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between PNPLA2 and NLSDM includes the biochemical function of the gene product (patatin-like phospholipase domain-containing protein, aka adipose triglyceride lipase) being consistent with the clinical and biochemical findings identified individuals with NLSDM (PMID: 17187067, PMID: 21544567), the biochemical and clinical features of a PNPLA2 knockout mouse animal (PMID: 16675698), and rescue of a PNPLA2 knockout mouse model via reexpression of a wild-type PNPLA2 transgene (PMID: 21857651). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, PNPLA2 is definitively associated with NLSDM. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on July 21, 2022 (SOP v9).

neutral lipid storage myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012545

Submitter: Ambry Genetics

neutral lipid storage myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012545

Submitter: G2P

neutral lipid storage myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012545

Submitter: Labcorp Genetics (formerly Invitae)

neutral lipid storage myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012545

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neutral lipid storage disease with myopathyAR

Manifestation: Dermatologic; Cardiovascular; Endocrine; Gastrointestinal; Musculoskeletal

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: 17187067; 22832386

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PNPLA2 variants in ClinVar

8 Conditions Cataloged

Neutral lipid storage myopathyTotal: 583

not providedTotal: 95

Inborn genetic diseasesTotal: 87

not specifiedTotal: 61

PNPLA2-related disorderTotal: 27

Abnormality of the musculatureTotal: 2

See casesTotal: 1

MyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020376.4. 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			6 clinvar	181 clinvar	1 clinvar	188
missense	4 clinvar	3 clinvar	263 clinvar	21 clinvar	1 clinvar	292
nonsense	6 clinvar	4 clinvar				10
start loss						0
frameshift	15 clinvar	7 clinvar	8 clinvar			30
splice donor/acceptor (+/-2bp)	3 clinvar	4 clinvar	4 clinvar			11
Total	28	18	281	202	2	531

Highest pathogenic variant AF is 0.00004579806

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020376.4	RefSeq	NP_065109.1	9	MANE Select
ENST00000336615.9	Ensembl	ENSP00000337701.4	9	MANE Select
ENST00000869283.1	Ensembl	ENSP00000539342.1	10	Standard
ENST00000869283.2	Ensembl	ENSP00000539342.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of lipolysis in adipocytes - Homo sapiens (human)
Glycerolipid metabolism - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)
Fatty Acid Beta Oxidation
Lipid storage and perilipins in skeletal muscle

Biological Process

negative regulation of sequestering of triglyceride
positive regulation of triglyceride catabolic process
triglyceride catabolic process
lipid storage
lipid droplet organization

Molecular Function

lipoprotein lipase activity
triglyceride lipase activity
acylglycerol O-acyltransferase activity

Cellular Component

nucleoplasm
cytoplasm
endoplasmic reticulum lumen
endoplasmic reticulum membrane
lipid droplet

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000336615
Coding exons: 9
Length: 6672
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125742
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.00894	308	308	1.00	0.0000216	3119
Missense (PolyPhen)		87	97.892	0.88873		1026
Synonymous	-0.548	156	148	1.06	0.0000112	1061
Loss of Function	2.36	7	17.8	0.394	8.52e-7	205

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00028	0.00027	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000076	0.000070	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the initial step in triglyceride hydrolysis in adipocyte and non-adipocyte lipid droplets (PubMed:15550674). Also has acylglycerol transacylase activity. May act coordinately with LIPE/HLS within the lipolytic cascade. Regulates adiposome size and may be involved in the degradation of adiposomes (PubMed:16239926). May play an important role in energy homeostasis. May play a role in the response of the organism to starvation, enhancing hydrolysis of triglycerides and providing free fatty acids to other tissues to be oxidized in situations of energy depletion. {ECO:0000269|PubMed:15364929, ECO:0000269|PubMed:15550674, ECO:0000269|PubMed:16239926}.;
Disease: DISEASE: Note=Genetic variations in PNPLA2 may be associated with risk of diabetes mellitus type 2. {ECO:0000269|PubMed:16644682}.; DISEASE: Neutral lipid storage disease with myopathy (NLSDM) [MIM:610717]: Neutral lipid storage disorder (NLSD) with myopathy but without ichthyosis. NLSDs are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Individuals with NLSDM did not show obesity, in spite of a defect in triglyceride degradation in fibroblasts and in marked triglyceride storage in liver, muscles, and other visceral cells. {ECO:0000269|PubMed:17187067}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.217

Intolerance Scores

LoFtool: 0.568
RVIS EVS: 0.04
RVIS percentile EVS: 57.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.691

Gene Damage Prediction

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