AGK

protein-coding

acylglycerol kinase

Gene summary

The protein encoded by this gene is a mitochondrial membrane protein involved in lipid and glycerolipid metabolism. The encoded protein is a lipid kinase that catalyzes the formation of phosphatidic and lysophosphatidic acids. Defects in this gene have been associated with mitochondrial DNA depletion syndrome 10. [provided by RefSeq, Feb 2012]

Previous symbols:

MULK

MANE transcript

NM_018238.4

Inheritance

AR, AD

ClinVar variants

P:55U:125B:82

Top phenotype

Sengers syndrome

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr7:141,551,278-141,655,244

External References & Databases

Ensembl (ENSG00000006530)

Transcript & Mutation Effects

hg38 • Region Span ~104.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Sengers syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008922

Submitter: PanelApp Australia

total early-onset cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0021548

Submitter: Orphanet

Sengers syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008922

Submitter: Orphanet

cataract 38LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013859

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *AGK* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 6, 2023. The *AGK* gene encodes mitochondrial acylglycerol kinase, a lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to generate lysophosphatidic acid and phosphatidic acid, respectively, in the inner mitochondrial membrane (IMM). Independent of its kinase activity, this protein also functions as a member of the TIM22 complex, which is required for the import of multi-pass transmembrane proteins into the IMM. The *AGK* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22284826), in several individuals with variable congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis (features seen in Sengers syndrome). While various names have been given to the constellation of features seen in those with *AGK*-related disease, including Sengers syndrome, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *AGK* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the gene-disease relationship between *AGK* and primary mitochondrial disease includes case-level data and experimental data. This curation includes eight variants (four nonsense, four frameshift) in five probands in three publications (PMIDs: 22284826, 25208612, 28868593) although additional cases have been reported in the medical literature. Affected individuals had bilateral cataracts, hypertrophic cardiomyopathy, skeletal myopathy, motor delay, hypotonia, and feeding difficulties. Metabolic screening labs showed lactic acidosis. Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by known biochemical function and in vitro functional assays demonstrating reduced rates of mitochondrial import due to variants in *AGK* (PMIDs: 33340416, 28712726). In summary, there is definitive evidence to support the relationship between *AGK* and autosomal recessive primary mitochondrial disease. More than three years have elapsed since the first assertion of this gene-disease relationship, and no contradictory evidence has emerged. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 6, 2023 (SOP Version 9).

Sengers syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008922

Submitter: Labcorp Genetics (formerly Invitae)

Sengers syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008922

Submitter: G2P

Clinical Genomic Database (CGD)

Sengers syndromeAR

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Biochemical; Cardiovascular

Rationale: Individuals can have cardiomyopathy, and early diagnosis may benefit medical management; Avoidance of factors that may precipitate lactic acidosis may be beneficial

Refs: 1168700; 3789054; 3560758; 3337009; 15168109; 16736096; 22415731; 22277967; 22284826; 23266196

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AGK variants in ClinVar

11 Conditions Cataloged

Sengers syndromeTotal: 267

Cataract 38Total: 248

not providedTotal: 108

Inborn genetic diseasesTotal: 68

not specifiedTotal: 52

AGK-related disorderTotal: 28

Mitochondrial diseaseTotal: 3

Hypercholesterolemia, familial, 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018238.4. 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	3 clinvar	64 clinvar		68
missense			117 clinvar	16 clinvar	1 clinvar	134
nonsense	18 clinvar	4 clinvar	1 clinvar			23
start loss	1 clinvar					1
frameshift	8 clinvar	7 clinvar	1 clinvar			16
splice donor/acceptor (+/-2bp)	8 clinvar	8 clinvar	3 clinvar	1 clinvar		20
Total	35	20	125	81	1	262

Highest pathogenic variant AF is 0.000081412174

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018238.4	RefSeq	NP_060708.1	15	MANE Select
ENST00000649286.2	Ensembl	ENSP00000497280.1	15	MANE Select
NM_001364948.3	RefSeq	NP_001351877.1	14	Standard
ENST00000473247.5	Ensembl	ENSP00000420776.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycerolipid metabolism - Homo sapiens (human)
Disease
Metabolism of lipids
Metabolism
Glycerophospholipid metabolism

Biological Process

protein insertion into mitochondrial inner membrane
glycerophospholipid biosynthetic process
ceramide biosynthetic process
lipid phosphorylation

Molecular Function

ceramide kinase activity
NAD+ kinase activity
diacylglycerol kinase activity
ATP binding
acylglycerol kinase activity

Cellular Component

mitochondrion
mitochondrial outer membrane
mitochondrial inner membrane
mitochondrial intermembrane space
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355413
Coding exons: 15
Length: 104056
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 125748
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.755	196	228	0.859	0.0000115	2749
Missense (PolyPhen)		45	56.286	0.79948		679
Synonymous	0.672	79	87.0	0.908	0.00000499	811
Loss of Function	2.08	18	30.4	0.592	0.00000175	316

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00070	0.00068	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00033	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00028	0.00027	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively (PubMed:15939762). Does not phosphorylate sphingosine (PubMed:15939762). Independently of its lipid kinase activity, acts as a component of the TIM22 complex (PubMed:28712724, PubMed:28712726). The TIM22 complex mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane by forming a twin-pore translocase that uses the membrane potential as the external driving force (PubMed:28712724, PubMed:28712726). In the TIM22 complex, required for the import of a subset of metabolite carriers into mitochondria, such as ANT1/SLC25A4 and SLC25A24, while it is not required for the import of TIMM23 (PubMed:28712724). Overexpression increases the formation and secretion of LPA, resulting in transactivation of EGFR and activation of the downstream MAPK signaling pathway, leading to increased cell growth (PubMed:15939762). {ECO:0000269|PubMed:15939762, ECO:0000269|PubMed:28712724, ECO:0000269|PubMed:28712726}.;
Disease: DISEASE: Mitochondrial DNA depletion syndrome 10 (MTDPS10) [MIM:212350]: An autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy. {ECO:0000269|PubMed:22277967, ECO:0000269|PubMed:22284826, ECO:0000269|PubMed:23266196, ECO:0000269|PubMed:25208612, ECO:0000269|PubMed:28712726}. Note=The disease is caused by mutations affecting the gene represented in this entry. The TIM22 complex and import of proteins into mitochondrion are affected in patients suffering of MTDPS10 (PubMed:28712726). {ECO:0000269|PubMed:28712726}.; DISEASE: Cataract 38 (CTRCT38) [MIM:614691]: An opacification of the crystalline lens of the eye becoming evident at birth. It frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. {ECO:0000269|PubMed:22415731}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.124

Intolerance Scores

LoFtool: 0.892
RVIS EVS: 0.4
RVIS percentile EVS: 76.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.878

Gene Damage Prediction

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