EPM2A

protein-coding

EPM2A glucan phosphatase, laforin, the group of Atypical dual specificity phosphatases

Gene summary

This gene encodes a dual-specificity phosphatase and may be involved in the regulation of glycogen metabolism. The protein acts on complex carbohydrates to prevent glycogen hyperphosphorylation, thus avoiding the formation of insoluble aggregates. Loss-of-function mutations in this gene have been associated with Lafora disease, a rare, adult-onset recessive neurodegenerative disease, which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of insoluble particles called Lafora bodies, which are derived from glycogen. [provided by RefSeq, Jan 2018]

MANE transcript

NM_005670.4

Inheritance

ClinVar variants

P:64U:223B:137

Top phenotype

Myoclonic epilepsy of Lafora 1

gnomAD constraint

pLI —, LoF o/e 0.77

Max pathogenic AF

—

Genomic locus

chr6:145,382,535-145,736,023

External References & Databases

Ensembl (ENSG00000112425)

UniProt (B3EWF7, O95278)

Transcript & Mutation Effects

hg38 • Region Span ~353.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Lafora diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: Orphanet

Lafora diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: PanelApp Australia

Lafora diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: ClinGen

Lafora disease (LD) is a fatal autosomal recessive form of adolescent-onset neurodegenerative disease, charaterized by progressive myoclonus epilepsy and neurodeterioration. The hallmark of the disease is presence of periodic acid-Schiff-positive polyglucosan inclusion bodies, called Lafora bodies. Mainly two genes, EPM2A and NHLRC1, have been associated with LD. LD was first reported to be associated with EPM2A in 1998 in a study that identified seven EPM2A variants in ten families (Minassian et al. 1998. PMID: 9771710). Since then, 32 deletions/insertions/frameshifts, 13 nonsense, and 57 missense variants have been identified in LD patients according to the Lafora Progressive Myoclonus Epilepsy Mutation and Polymorphism Database (http://projects.tcag.ca/lafora/). Nineteen symptomatic probands from 19 families with homozygous or compound heterozygous EPM2A variants studied by six studies were scored for genetic evidence (PMID: 9771710, 9931343, 11175283, 12019207, 12560877, 14722920). While many of the variants were unique to each family, one variant, c. 721C>T; p.Arg241* in NM_005670.3, has a relatively high occurrence due to both founder effect and recurrence verified by a haplotype study (11175283). Nine probands had two variants in trans that were not predicted/proven to be null, and were given scores ranging from 0 to 1. The remaining ten probands had at least one of the two variants in trans that were proven/predicted to be null, and were given scores ranging from 1 to 2. Functional studies rather than presence of Lafora bodies were used to upgrade the points for some studies (9771710, 9931343, 11175283, 12560877), because presence of Lafora bodies were documented only as a study inclusion statement in the methods section, and/or only EPM2A was studied. No LOD scores could be calculated from these families, because only single affected individual was reported for each case. Supporting experimental evidence includes expression (11355878), protein interaction (15930137), non-human model organism (12019206), and rescue in non-human model organism (24430976). In summary, a score of 12 was given to genetic evidence, and 4 to experimental evidence, reaching 16 in total. EPM2A’s association with LD is upgraded from strong to definitive, because it has been replicated for more than 2 decades.

Lafora diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: Labcorp Genetics (formerly Invitae)

Lafora diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Myoclonic epilepsy of Lafora 1AR

Manifestation: Neurologic

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

Comments: Some antiepileptic drugs may be effective, but certain medications (eg, phenytoin, and possibly carbamazepine, oxcarbazepine, and lamotrigine) can exacerbate myoclonus

Refs: 9771710; 10513696; 14663053; 15277643; 16157917; 16356781; 20301563

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPM2A variants in ClinVar

15 Conditions Cataloged

Progressive myoclonic epilepsyTotal: 361

not providedTotal: 119

Inborn genetic diseasesTotal: 94

Lafora diseaseTotal: 71

not specifiedTotal: 40

Myoclonic epilepsy of Lafora 1Total: 30

EPM2A-related disorderTotal: 15

EPM2A-related disordersTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005670.4. 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	127 clinvar	1 clinvar	129
missense	2 clinvar	22 clinvar	219 clinvar	8 clinvar	1 clinvar	252
nonsense	7 clinvar	7 clinvar	1 clinvar			15
start loss						0
frameshift	12 clinvar	8 clinvar	1 clinvar			21
splice donor/acceptor (+/-2bp)	4 clinvar	2 clinvar	1 clinvar			7
Total	25	39	223	135	2	424

Highest pathogenic variant AF is 0.00010781858

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005670.4	RefSeq	NP_005661.1	4	MANE Select
ENST00000367519.9	Ensembl	ENSP00000356489.3	4	MANE Select
NM_001018041.2	RefSeq	NP_001018051.1	5	Standard
NM_001360057.2	RefSeq	NP_001346986.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of carbohydrates
Metabolism
Glycogen synthesis
Glycogen metabolism

Biological Process

positive regulation of macroautophagy
negative regulation of TOR signaling

Molecular Function

protein binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367519
Coding exons: 4
Length: 234442
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125748
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.260	165	156	1.06	0.00000893	2124
Missense (PolyPhen)		64	59.944	1.0677		676
Synonymous	-1.64	78	61.6	1.27	0.00000373	660
Loss of Function	0.733	9	11.7	0.769	5.89e-7	141

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.325

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.675

Gene Damage Prediction

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