LPIN1

protein-coding

lipin 1, the group of MicroRNA protein coding host genes|Lipins

Gene summary

This gene encodes a magnesium-ion-dependent phosphatidic acid phosphohydrolase enzyme that catalyzes the penultimate step in triglyceride synthesis including the dephosphorylation of phosphatidic acid to yield diacylglycerol. Expression of this gene is required for adipocyte differentiation and it also functions as a nuclear transcriptional coactivator with some peroxisome proliferator-activated receptors to modulate expression of other genes involved in lipid metabolism. Mutations in this gene are associated with metabolic syndrome, type 2 diabetes, acute recurrent rhabdomyolysis, and autosomal recessive acute recurrent myoglobinuria (ARARM). This gene is also a candidate for several human lipodystrophy syndromes. [provided by RefSeq, Mar 2017]

MANE transcript

NM_001349206.2

Inheritance

AR, AD

ClinVar variants

P:60U:296B:202

Top phenotype

Myoglobinuria, acute, recurrent, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr2:11,677,595-11,827,409

External References & Databases

Ensembl (ENSG00000134324)

Transcript & Mutation Effects

hg38 • Region Span ~149.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myoglobinuria, acute recurrent, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009992

Submitter: Ambry Genetics

myoglobinuria, acute recurrent, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009992

Submitter: ClinGen

myoglobinuria, acute recurrent, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009992

Submitter: PanelApp Australia

myoglobinuria, acute recurrent, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009992

Submitter: Labcorp Genetics (formerly Invitae)

hereditary recurrent myoglobinuriaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020504

Submitter: Orphanet

myoglobinuria, acute recurrent, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009992

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Myoglobinuria, acute, recurrent, autosomal recessiveAR

Manifestation: Musculoskeletal; Renal

Intervention: Musculoskeletal; Pharmacogenomic; Renal

Rationale: Attacks are typically trigerred by illnesses rather than exercise, and avoidance of fasting and prompt treatment of febrile illness may prevent severe sequelae such as renal failure; Anesthesia precautions can be beneficial in order to decrease the risk of malignant hyperthermia

Refs: 6851679; 1544519; 18817903

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LPIN1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 560

Myoglobinuria, acute recurrent, autosomal recessiveTotal: 224

Inborn genetic diseasesTotal: 113

LPIN1-related disorderTotal: 39

not specifiedTotal: 38

Acute rhabdomyolysisTotal: 3

See casesTotal: 2

Other rare neuromuscular disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001349206.2. 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	4 clinvar	184 clinvar	4 clinvar	193
missense	1 clinvar	3 clinvar	285 clinvar	13 clinvar	1 clinvar	303
nonsense	12 clinvar	3 clinvar	1 clinvar			16
start loss						0
frameshift	16 clinvar	13 clinvar	1 clinvar			30
splice donor/acceptor (+/-2bp)	2 clinvar	9 clinvar	5 clinvar			16
Total	31	29	296	197	5	558

Highest pathogenic variant AF is 0.00003407742

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 87 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001349206.2	RefSeq	NP_001336135.1	20	MANE Select
ENST00000674199.1	Ensembl	ENSP00000501331.1	20	MANE Select
NM_001261427.3	RefSeq	NP_001248356.1	20	Standard
NM_001261428.3	RefSeq	NP_001248357.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mTOR signaling pathway - Homo sapiens (human)
Glycerolipid metabolism - Homo sapiens (human)
Glycerophospholipid metabolism - Homo sapiens (human)
Sterol Regulatory Element-Binding Proteins (SREBP) signalling
Adipogenesis

Biological Process

triglyceride mobilization
phosphatidylethanolamine biosynthetic process
phosphatidylcholine biosynthetic process
mitotic nuclear envelope disassembly
fatty acid catabolic process

Molecular Function

molecular_function
transcription coactivator activity
phosphatidate phosphatase activity

Cellular Component

nucleus
nuclear envelope
nucleoplasm
cytoplasm
mitochondrial outer membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000449576
Coding exons: 22
Length: 149815
Individuals with no LoFs: 125688
Homozygous LoFs: 0
Heterozygous LoFs: 60
Defined: 125748
p: 0.000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.869	499	557	0.896	0.0000314	6397
Missense (PolyPhen)		169	211.94	0.79738		2406
Synonymous	0.153	230	233	0.987	0.0000153	1883
Loss of Function	3.19	29	54.4	0.533	0.00000292	601

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00037	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.00029	0.00029	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays important roles in controlling the metabolism of fatty acids at different levels. Acts as a magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis in the reticulum endoplasmic membrane. Acts also as a nuclear transcriptional coactivator for PPARGC1A/PPARA to modulate lipid metabolism gene expression (By similarity). Is involved in adipocyte differentiation. May also be involved in mitochondrial fission by converting phosphatidic acid to diacylglycerol (By similarity). {ECO:0000250}.;
Disease: DISEASE: Myoglobinuria, acute recurrent, autosomal recessive (ARARM) [MIM:268200]: Recurrent myoglobinuria is characterized by recurrent attacks of rhabdomyolysis (necrosis or disintegration of skeletal muscle) associated with muscle pain and weakness and followed by excretion of myoglobin in the urine. Renal failure may occasionally occur. {ECO:0000269|PubMed:18817903}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.174

Intolerance Scores

LoFtool: 0.359
RVIS EVS: -1.19
RVIS percentile EVS: 5.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.889

Gene Damage Prediction

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