myoclonic epilepsy of Lafora 1

Summary

myoclonic epilepsy of Lafora 1 (MONDO:0958199) is a disease caused by NHLRC1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: NHLRC1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myoclonic epilepsy of Lafora 1
Mondo ID	MONDO:0958199
OMIM	254780
DOID	DOID:0070660
GARD	0026971
Is cancer (heuristic)	no

Data availability: 35 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism › Lafora disease › myoclonic epilepsy of Lafora 1

Related subtypes (1): myoclonic epilepsy of Lafora 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

35 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 6 conflicting classifications of pathogenicity, 6 pathogenic, 6 likely pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075527	NM_005670.4(EPM2A):c.108_139del (p.Ala37fs)	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1322827	NM_005670.4(EPM2A):c.322del (p.Arg108fs)	EPM2A	Pathogenic	criteria provided, single submitter
205431	NM_005670.4(EPM2A):c.166G>T (p.Glu56Ter)	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
3098	NM_005670.4(EPM2A):c.721C>T (p.Arg241Ter)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3099	NM_005670.4(EPM2A):c.835G>A (p.Gly279Ser)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3100	NM_005670.4(EPM2A):c.322C>T (p.Arg108Cys)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3101	NM_005670.4(EPM2A):c.335dup (p.Tyr112Ter)	EPM2A	Pathogenic	criteria provided, single submitter
3102	NM_005670.4(EPM2A):c.512G>A (p.Arg171His)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3107	NM_005670.4(EPM2A):c.94T>G (p.Trp32Gly)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776209	NM_005670.4(EPM2A):c.43_159del (p.Gly15_Ala53del)	EPM2A	Pathogenic	criteria provided, single submitter
419335	NM_005670.4(EPM2A):c.163C>T (p.Gln55Ter)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2587	NM_198586.3(NHLRC1):c.205C>G (p.Pro69Ala)	NHLRC1	Pathogenic	criteria provided, multiple submitters, no conflicts
3065483	NM_005670.4(EPM2A):c.263T>A (p.Phe88Tyr)	EPM2A	Likely pathogenic	criteria provided, single submitter
3065607	NM_005670.4(EPM2A):c.177del (p.Trp60fs)	EPM2A	Likely pathogenic	criteria provided, single submitter
3106	NM_005670.4(EPM2A):c.953dup (p.Gln319fs)	EPM2A	Likely pathogenic	criteria provided, single submitter
3340091	NM_005670.4(EPM2A):c.301+1G>C	EPM2A	Likely pathogenic	criteria provided, single submitter
3234973	NM_005670.4(EPM2A):c.82_154del (p.Glu28fs)	LOC129997381	Likely pathogenic	criteria provided, single submitter
3370489	NM_005670.4(EPM2A):c.135del (p.Ala46fs)	LOC129997381	Likely pathogenic	criteria provided, single submitter
1013308	NM_005670.4(EPM2A):c.290T>G (p.Leu97Arg)	EPM2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205435	NM_005670.4(EPM2A):c.722G>A (p.Arg241Gln)	EPM2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411297	NM_005670.4(EPM2A):c.743C>T (p.Ala248Val)	EPM2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167350	NM_198586.3(NHLRC1):c.32C>A (p.Ala11Glu)	NHLRC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193518	NM_198586.3(NHLRC1):c.46A>G (p.Met16Val)	NHLRC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
206189	NM_198586.3(NHLRC1):c.478T>C (p.Cys160Arg)	NHLRC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019461	NM_005670.4(EPM2A):c.215C>T (p.Ala72Val)	EPM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
205424	NM_005670.4(EPM2A):c.148G>A (p.Gly50Arg)	EPM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
205429	NM_005670.4(EPM2A):c.644A>T (p.Asp215Val)	EPM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
205433	NM_005670.4(EPM2A):c.209A>T (p.Glu70Val)	EPM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
205444	NM_005670.4(EPM2A):c.136G>A (p.Ala46Thr)	EPM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377580	NM_005670.4(EPM2A):c.377T>C (p.Ile126Thr)	EPM2A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NHLRC1	Definitive	Autosomal recessive	Lafora disease	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NHLRC1	Orphanet:501	Lafora disease
EPM2A	Orphanet:501	Lafora disease

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NHLRC1	HGNC:21576	ENSG00000187566	Q6VVB1	E3 ubiquitin-protein ligase NHLRC1	gencc,clinvar
EPM2A	HGNC:3413	ENSG00000112425	B3EWF7	Laforin, isoform 9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NHLRC1	E3 ubiquitin-protein ligase NHLRC1	E3 ubiquitin-protein ligase.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Phosphatase	1	42.0×	0.047
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NHLRC1	Transcription factor	no		NHL_repeat, Znf_RING, 6-blade_b-propeller_TolB-like
EPM2A	Phosphatase	yes	3.1.3.16	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, CBM20

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	2
islet of Langerhans	1
prefrontal cortex	1
biceps brachii	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NHLRC1	129	broad	yes	prefrontal cortex, islet of Langerhans, hindlimb stylopod muscle
EPM2A	281	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NHLRC1	939
EPM2A	4

Intra-cohort edges

A	B	Sources
EPM2A	NHLRC1	biogrid_interaction, intact

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPM2A	B3EWF7	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NHLRC1	Q6VVB1	85.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Myoclonic epilepsy of Lafora	2	1268.9×	1e-06	NHLRC1, EPM2A
Glycogen synthesis	2	815.7×	1e-06	NHLRC1, EPM2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycogen biosynthetic process	2	936.2×	3e-05	NHLRC1, EPM2A
regulation of protein localization to plasma membrane	2	648.1×	4e-05	NHLRC1, EPM2A
negative regulation of phosphatase activity	1	2808.7×	0.002	EPM2A
negative regulation of dephosphorylation	1	2106.5×	0.002	EPM2A
habituation	1	2106.5×	0.002	EPM2A
proteasome-mediated ubiquitin-dependent protein catabolic process	2	52.2×	0.002	NHLRC1, EPM2A
regulation of protein import into nucleus	1	1685.2×	0.003	EPM2A
carbohydrate phosphorylation	1	1053.2×	0.004	EPM2A
glial cell proliferation	1	443.5×	0.006	EPM2A
regulation of protein ubiquitination	1	443.5×	0.006	EPM2A
peptidyl-tyrosine dephosphorylation	1	443.5×	0.006	EPM2A
L-glutamate transmembrane transport	1	401.2×	0.006	EPM2A
regulation of proteasomal protein catabolic process	1	383.0×	0.006	EPM2A
dephosphorylation	1	337.0×	0.007	EPM2A
negative regulation of TOR signaling	1	280.9×	0.007	EPM2A
glycogen metabolic process	1	263.3×	0.007	EPM2A
positive regulation of macroautophagy	1	263.3×	0.007	EPM2A
negative regulation of cell cycle	1	145.3×	0.012	EPM2A
autophagosome assembly	1	112.3×	0.013	EPM2A
regulation of cell growth	1	110.9×	0.013	EPM2A
protein dephosphorylation	1	110.9×	0.013	EPM2A
positive regulation of protein ubiquitination	1	106.7×	0.013	NHLRC1
calcium ion transport	1	90.6×	0.015	EPM2A
response to endoplasmic reticulum stress	1	83.4×	0.015	NHLRC1
mitochondrion organization	1	75.9×	0.016	EPM2A
protein polyubiquitination	1	57.7×	0.021	NHLRC1
autophagy	1	55.1×	0.021	NHLRC1
Wnt signaling pathway	1	49.9×	0.022	EPM2A
regulation of gene expression	1	41.7×	0.025	NHLRC1
ubiquitin-dependent protein catabolic process	1	37.1×	0.028	NHLRC1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NHLRC1	0	0
EPM2A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPM2A	3.1.3.16	protein-serine/threonine phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	EPM2A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NHLRC1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NHLRC1	0	—
EPM2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.