NHLRC1

Summary

NHLRC1 (NHL repeat containing E3 ubiquitin protein ligase 1, HGNC:21576) is a protein-coding gene on chromosome 6p22.3, encoding E3 ubiquitin-protein ligase NHLRC1 (Q6VVB1). E3 ubiquitin-protein ligase.

The protein encoded by this gene is a single subunit E3 ubiquitin ligase. Laforin is polyubiquitinated by the encoded protein. Defects in this intronless gene lead to an accumulation of laforin and onset of Lafora disease, also known as progressive myoclonic epilepsy type 2 (EPM2).

Source: NCBI Gene 378884 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Lafora disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 380 total — 32 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 42
• MANE Select transcript: NM_198586

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21576
Approved symbol	NHLRC1
Name	NHL repeat containing E3 ubiquitin protein ligase 1
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Aliases	bA204B7.2, EPM2B
Ensembl gene	ENSG00000187566
Ensembl biotype	protein_coding
OMIM	608072
Entrez	378884

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000340650

RefSeq mRNA: 1 — MANE Select: NM_198586 NM_198586

CCDS: CCDS4542

Canonical transcript exons

ENST00000340650 — 1 exons

Exon	Start	End
ENSE00001967327	18120440	18122677

Expression profiles

Bgee: expression breadth ubiquitous, 129 present calls, max score 70.84.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0706 / max 13.8128, expressed in 707 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72017	1.0706	707

Top tissues by expression

132 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	70.84	gold quality
islet of Langerhans	UBERON:0000006	70.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	69.87	gold quality
right lobe of liver	UBERON:0001114	69.83	gold quality
superior frontal gyrus	UBERON:0002661	69.38	gold quality
frontal cortex	UBERON:0001870	68.60	gold quality
muscle of leg	UBERON:0001383	68.44	gold quality
stromal cell of endometrium	CL:0002255	68.21	gold quality
gastrocnemius	UBERON:0001388	68.11	gold quality
Brodmann (1909) area 9	UBERON:0013540	67.58	gold quality
cortical plate	UBERON:0005343	67.46	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	67.13	gold quality
skin of leg	UBERON:0001511	67.01	gold quality
cerebral cortex	UBERON:0000956	66.97	gold quality
right adrenal gland	UBERON:0001233	66.73	gold quality
zone of skin	UBERON:0000014	66.70	gold quality
putamen	UBERON:0001874	66.66	gold quality
primary visual cortex	UBERON:0002436	66.63	gold quality
liver	UBERON:0002107	66.56	gold quality
skeletal muscle tissue	UBERON:0001134	66.50	gold quality
skin of abdomen	UBERON:0001416	66.27	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	66.25	gold quality
nucleus accumbens	UBERON:0001882	66.15	gold quality
right adrenal gland cortex	UBERON:0035827	66.15	gold quality
substantia nigra	UBERON:0002038	65.58	gold quality
anterior cingulate cortex	UBERON:0009835	65.43	gold quality
right frontal lobe	UBERON:0002810	65.31	gold quality
apex of heart	UBERON:0002098	65.17	gold quality
caudate nucleus	UBERON:0001873	65.08	gold quality
leukocyte	CL:0000738	65.03	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting NHLRC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-574-5P	100.00	66.01	989
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817

Literature-anchored findings (GeneRIF, showing 36)

• Laforin and malin colocalize to the ER, suggesting they operate in a related pathway protecting against polyglucosan accumulation and epilepsy (PMID:12958597)
• Genetic allelic heterogeneity is present in Lafora disease associated with mutations in EPM2B. Patients with mutations in EPM2A and EPM2B express similar clinical manifestation. (PMID:15781812)
• Malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. (PMID:15930137)
• Malin is an E3 ubiquitin ligase that binds glycogen synthase. (PMID:16115820)
• Patients with NHLRC1 mutations have a slower rate of disease progression than those with EPM2A mutations. (PMID:16950819)
• Defects in malin may lead to increased levels of misfolded and/or target proteins, which may eventually affect the physiological processes of the neuron, and likely to be the primary trigger in the physiopathology of lafora disease. (PMID:17337485)
• Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase complex pathway. (PMID:18029386)
• The phosphatase laforin acts as a scaffold that allows malin to ubiquitinate protein targeting to glycogen (PTG). These results suggest an additional mechanism, involving laforin and malin, in regulating glycogen metabolism. (PMID:18070875)
• malin ubiquitinates PTG in a laforin-dependent manner, both in vivo and in vitro, and targets PTG for proteasome-dependent degradation. These results suggest an additional mechanism, involving laforin and malin, in regulating glycogen metabolism (PMID:18070875)
• The authors identified 14 Lafora epilepsy patients in the genetic isolate of tribal Oman. The authors show that in this homogeneous environment and gene pool, the same mutation, EPM2B-c.468-469delAG, results in highly uniform ages of onset and death. (PMID:18263761)
• Results suggest that the altered subcellular localization of mutant proteins of the EPM2A and NHLRC1 genes could be one of the molecular bases of the Lafora disease phenotype. (PMID:18311786)
• Laforin and malin interact with misfolded proteins and promote their degradation through the ubiquitin-proteasome system. (PMID:19036738)
• phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity. (PMID:19171932)
• Results describe a novel homozygous single-nucleotide variant in the NHLRC1 gene in a Malian consanguineous family. (PMID:19322595)
• laforin and malin play a role protecting cells from ER-stress, likely contributing to the elimination of unfolded proteins (PMID:19529779)
• the co-chaperone carboxyl terminus of the Hsc70-interacting protein (CHIP) stabilizes malin by modulating the activity of Hsp70. (PMID:19892702)
• These results suggest that the modification introduced by the laforin-malin complex could affect the subcellular distribution of AMPK beta subunits. (PMID:20534808)
• study described several novel mutations of EPM2A and NHLRC1 and brought additional data to genetic epidemiology of Lafora disease (LD); emphasized the high mutation rate in patients with classical LD as well as the high negativity rate of skin biopsy (PMID:20738377)
• malin(C46Y), malin(P69A), malin(D146N), and malin(L261P) mutants failed to downregulate the level of R5/PTG, a regulatory subunit of protein phosphatase 1 involved in glycogen synthesis. (PMID:21505799)
• Mutations in the NHL repeat containing 1 (NHLRC1) gene are described in association with a more benign clinical course and later age of death in an adolescent patient. (PMID:21555062)
• Laforin and malin are defective in Lafora disease (LD), a neurodegenerative disorder associated with epileptic seizures (PMID:21652633)
• malin negatively regulates neuronatin and its loss of function in Lafora disease results in increased accumulation of neuronatin (PMID:21742036)
• Malin is related to TRIM32 at both the phylogenetic and functional level. (PMID:21798009)
• This study identified that NHLRC1 gene mutations leading to Lafora disease in six Turkish families. (PMID:22047982)
• Our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease. (PMID:22223637)
• Malin forms a functional complex with laforin. This complex promotes the ubiquitination of proteins involved in glycogen metabolism and misregulation of pathways involved in this process results in Lafora body formation. (Review) (PMID:22815132)
• Malin regulates the recruitment of mRNA-decapping enzyme 1A (Dcp1a) to processing bodies. (PMID:23131811)
• Without functional laforin-malin complex assembled on polyglucosan bodies, polyglucosan is not degraded. (PMID:24068615)
• This study demonistrated that NHLRC1 mutations were detected in some case of Mild Lafora disease patients. (PMID:25270369)
• Lafora disease proteins laforin and malin negatively regulate the HIPK2-p53 cell death pathway. (PMID:26102034)
• laforin/malin complex is able to interact with and ubiquitinate both PKM1 and PKM2 (PMID:26493215)
• Malin promotes its own degradation via auto-ubiquitination.Malin preferentially degrades the phosphatase-inactive laforin monomer. (PMID:26648032)
• Laforin/malin complex interacts physically and co-localizes intracellularly with core components of the PI3KC3 complex (Beclin1, Vps34 and Vps15), and that this interaction is specific and results in the polyubiquitination of these proteins. (PMID:31758957)
• The rare rs769301934 variant in NHLRC1 is a common cause of Lafora disease in Turkey. (PMID:34117373)
• Compound heterozygosity for novel variations of the NHLRC1 Gene in a family with Lafora disease. (PMID:35569391)
• Identification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS). (PMID:36142605)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nhlrc1	ENSMUSG00000044231
rattus_norvegicus	Nhlrc1	ENSRNOG00000026286

Protein

Protein identifiers

E3 ubiquitin-protein ligase NHLRC1 — Q6VVB1 (reviewed: Q6VVB1)

Alternative names: Malin, NHL repeat-containing protein 1, RING-type E3 ubiquitin transferase NHLRC1

All UniProt accessions (1): Q6VVB1

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase. Together with the phosphatase EPM2A/laforin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. In complex with EPM2A/laforin and HSP70, suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Ubiquitinates the glycogen-targeting protein phosphatase subunits PPP1R3C/PTG and PPP1R3D in a laforin-dependent manner and targets them for proteasome-dependent degradation, thus decreasing glycogen accumulation. Polyubiquitinates EPM2A/laforin and ubiquitinates AGL and targets them for proteasome-dependent degradation. Also promotes proteasome-independent protein degradation through the macroautophagy pathway.

Subunit / interactions. Interacts with AGL. Interacts (via the NHL repeats) with EPM2A/laforin. Forms a complex with EPM2A/laforin and HSP70. Interacts with PRDM8.

Subcellular location. Endoplasmic reticulum. Nucleus.

Tissue specificity. Expressed in brain, cerebellum, spinal cord, medulla, heart, liver, skeletal muscle and pancreas.

Disease relevance. Myoclonic epilepsy of Lafora 2 (MELF2) [MIM:620681] A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. MELF2 is an autosomal recessive, severe form characterized by onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, myoclonic jerks, generalized seizures, and often visual hallucination. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. At the cellular level, MELF2 is characterized by accumulation of starch-like polyglucosans called Lafora bodies (LBs) that are most abundant in organs with the highest glucose metabolism: brain, heart, liver and skeletal muscle. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RING domain is essential for ubiquitin E3 ligase activity.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_940988* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001258	NHL_repeat	Repeat
IPR001841	Znf_RING	Domain
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR050952	TRIM-NHL_E3_ligases	Family

Pfam: PF14634

UniProt features (33 total): sequence variant 24, repeat 6, chain 1, mutagenesis site 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6VVB1-F1	85.87	0.55

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
280	loss of interaction with ep2ma.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3322077	Glycogen synthesis
R-HSA-3785653	Myoclonic epilepsy of Lafora

MSigDB gene sets: 173 (showing top): GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, KEGG_UBIQUITIN_MEDIATED_PROTEOLYSIS, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GOBP_PROTEIN_CATABOLIC_PROCESS, REACTOME_METABOLISM_OF_CARBOHYDRATES_AND_CARBOHYDRATE_DERIVATIVES, GOBP_PROTEOLYSIS

GO Biological Process (12): protein polyubiquitination (GO:0000209), glycogen biosynthetic process (GO:0005978), ubiquitin-dependent protein catabolic process (GO:0006511), autophagy (GO:0006914), regulation of gene expression (GO:0010468), positive regulation of protein ubiquitination (GO:0031398), response to endoplasmic reticulum stress (GO:0034976), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of protein localization to plasma membrane (GO:1903076), glycogen metabolic process (GO:0005977), protein ubiquitination (GO:0016567), regulation of protein ubiquitination (GO:0031396)

GO Molecular Function (6): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glycogen metabolism	1
Glycogen storage diseases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	4
cellular anatomical structure	4
cytoplasm	3
intracellular membrane-bounded organelle	2
glycogen metabolic process	1
glucan biosynthetic process	1
modification-dependent protein catabolic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
gene expression	1
regulation of macromolecule biosynthetic process	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
cellular response to stress	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein localization to plasma membrane	1
regulation of protein localization to cell periphery	1
regulation of protein localization to membrane	1
energy reserve metabolic process	1
glucan metabolic process	1
protein modification by small protein conjugation	1
regulation of protein modification by small protein conjugation or removal	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
endomembrane system	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHLRC1	EPM2A	O95278	999
NHLRC1	GYS1	P13807	877
NHLRC1	AGL	P35573	871
NHLRC1	PPP1R3C	Q9UQK1	841
NHLRC1	CSTB	P04080	822
NHLRC1	PRDM8	Q9NQV8	730
NHLRC1	KCTD7	Q96MP8	725
NHLRC1	EPM2AIP1	Q7L775	689
NHLRC1	PRICKLE1	Q96MT3	680
NHLRC1	GBE1	Q04446	610
NHLRC1	NFU1	Q9UMS0	608
NHLRC1	UBE2E1	P51965	555
NHLRC1	TXNL1	O43396	551
NHLRC1	SCGN	O76038	543
NHLRC1	UBE2D1	P51668	542

IntAct

30 interactions, top by confidence:

A	B	Type	Score
EPM2A	NHLRC1	psi-mi:“MI:0403”(colocalization)	0.790
EPM2A	NHLRC1	psi-mi:“MI:0915”(physical association)	0.790
NHLRC1	EPM2A	psi-mi:“MI:0915”(physical association)	0.790
NHLRC1	Epm2a	psi-mi:“MI:0915”(physical association)	0.500
Epm2a	NHLRC1	psi-mi:“MI:0915”(physical association)	0.500
NHLRC1	Epm2a	psi-mi:“MI:0914”(association)	0.500
NHLRC1	UBA1	psi-mi:“MI:0915”(physical association)	0.400
EPM2A	UBA1	psi-mi:“MI:0915”(physical association)	0.400
HSP90AB1	NHLRC1	psi-mi:“MI:0915”(physical association)	0.400
NHLRC1	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
NUDC	NHLRC1	psi-mi:“MI:0915”(physical association)	0.400
NHLRC1	NUDCD3	psi-mi:“MI:0915”(physical association)	0.400
NHLRC1		psi-mi:“MI:0915”(physical association)	0.400
NHLRC1	TK2	psi-mi:“MI:0914”(association)	0.350

BioGRID (61): UBE2H (Reconstituted Complex), UBE2D1 (Reconstituted Complex), UBE2D3 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), EPM2A (Reconstituted Complex), GYS1 (Reconstituted Complex), NHLRC1 (Two-hybrid), NHLRC1 (Two-hybrid), NHLRC1 (Affinity Capture-Western), EPM2A (Reconstituted Complex), NHLRC1 (Affinity Capture-Western), NHLRC1 (Affinity Capture-Western), NHLRC1 (Two-hybrid), BECN1 (Affinity Capture-Western), NHLRC1 (Affinity Capture-Western)

ESM2 similar proteins: A6QP75, D3YWP0, O95294, P0CG21, P57737, P57775, Q0D2K2, Q0V8F1, Q2TBI8, Q3SZD4, Q3T0A0, Q3UP44, Q4FZD7, Q58D06, Q5E9V4, Q5H879, Q5RBW3, Q60I27, Q63148, Q6AYG0, Q6IMG5, Q6Q7D1, Q6RFH5, Q6VVB1, Q86UR1, Q86VU5, Q8BIG7, Q8BR37, Q8C3F7, Q8K1S1, Q8N135, Q8N9H8, Q8NEP7, Q8TCX5, Q8VCG3, Q8VHS5, Q8WWP7, Q8WXI3, Q91ZT7, Q969S8

Diamond homologs: E1BD59, E7ERA6, M0QZC1, Q3SWY0, Q3UV31, Q5ZMD4, Q6IMG5, Q6VVB1, Q8BR37, Q8IWR1, Q8QZS5, Q96D59, Q9BRZ2, Q9D241, Q9D7D1, A5D8S5, D2H6Z0, D2H788, D3ZBM4, D4A723, E1C2W7, O60858, P0CG21, Q11072, Q13049, Q32L60, Q3UP44, Q4VGL6, Q58EC8, Q5M7V1, Q5TC82, Q68EV7, Q6GND7, Q6INB3, Q6NUC6, Q810I1, Q810I2, Q865W2, Q86UV6, Q86UV7

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	NHLRC1	ubiquitination
NHLRC1	“down-regulates quantity by destabilization”	EPM2A	polyubiquitination
NHLRC1	“down-regulates quantity by destabilization”	PPP1R3C	ubiquitination
NHLRC1	“down-regulates quantity by destabilization”	PPP1R3B	ubiquitination
NHLRC1	“down-regulates quantity by destabilization”	DVL2	polyubiquitination
NHLRC1	“up-regulates activity”	SLC1A2	ubiquitination
EPM2A	“up-regulates activity”	NHLRC1	binding
NHLRC1	“down-regulates quantity by destabilization”	AGL	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

380 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	14
Uncertain significance	211
Likely benign	84
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1029356	NM_198586.3(NHLRC1):c.368G>A (p.Trp123Ter)	Pathogenic
1069688	NM_198586.3(NHLRC1):c.799del (p.Val267fs)	Pathogenic
1071786	NM_198586.3(NHLRC1):c.670_673del (p.Thr224fs)	Pathogenic
1299569	NM_198586.3(NHLRC1):c.583del (p.Asp195fs)	Pathogenic
1412922	NM_198586.3(NHLRC1):c.37_38insTC (p.His13fs)	Pathogenic
1452637	NM_198586.3(NHLRC1):c.865_880del (p.Gly288_Val289insTer)	Pathogenic
1453372	NM_198586.3(NHLRC1):c.799dup (p.Val267fs)	Pathogenic
1460040	NC_000006.11:g.(?18121650)(18149358_?)del	Pathogenic
193517	NM_198586.3(NHLRC1):c.664G>T (p.Glu222Ter)	Pathogenic
206194	NM_198586.3(NHLRC1):c.226del (p.Arg76fs)	Pathogenic
2571244	NM_198586.3(NHLRC1):c.1049_1050del (p.Glu350fs)	Pathogenic
2586	NM_198586.3(NHLRC1):c.76T>A (p.Cys26Ser)	Pathogenic
2587	NM_198586.3(NHLRC1):c.205C>G (p.Pro69Ala)	Pathogenic
2588	NM_198586.3(NHLRC1):c.468_469del (p.Gly158fs)	Pathogenic
2589	NM_198586.3(NHLRC1):c.992del (p.Gly331fs)	Pathogenic
2590	NM_198586.3(NHLRC1):c.793C>T (p.Arg265Ter)	Pathogenic
2592	NM_198586.3(NHLRC1):c.923A>C (p.Asp308Ala)	Pathogenic
2717577	NM_198586.3(NHLRC1):c.558_562del (p.His187fs)	Pathogenic
2734827	NM_198586.3(NHLRC1):c.137G>A (p.Cys46Tyr)	Pathogenic
280034	NM_198586.3(NHLRC1):c.468del (p.Gly158fs)	Pathogenic
2812879	NM_198586.3(NHLRC1):c.230del (p.Gly77fs)	Pathogenic
2829900	NM_198586.3(NHLRC1):c.742del (p.Glu248fs)	Pathogenic
2863829	NM_198586.3(NHLRC1):c.1120G>T (p.Glu374Ter)	Pathogenic
2991106	NM_198586.3(NHLRC1):c.519del (p.Asp173fs)	Pathogenic
3336988	NM_198586.3(NHLRC1):c.332_333insT (p.Gly112fs)	Pathogenic
3720675	NM_198586.3(NHLRC1):c.940_943dup (p.Tyr315fs)	Pathogenic
3720676	NM_198586.3(NHLRC1):c.98T>C (p.Phe33Ser)	Pathogenic
4724562	NM_198586.3(NHLRC1):c.1110dup (p.Phe371fs)	Pathogenic
663551	NM_198586.3(NHLRC1):c.462dup (p.Asp155Ter)	Pathogenic
860910	NM_198586.3(NHLRC1):c.1091C>A (p.Ser364Ter)	Pathogenic

SpliceAI

315 predictions. Top by Δscore:

Variant	Effect	Δscore
6:18122162:T:TA	donor_gain	0.6500
6:18121673:G:C	donor_gain	0.6200
6:18121672:AG:A	donor_gain	0.5900
6:18122136:C:CA	donor_gain	0.5700
6:18121719:CACTT:C	donor_gain	0.5600
6:18122459:C:CT	donor_gain	0.5400
6:18121740:A:T	donor_gain	0.5300
6:18122085:A:AC	donor_gain	0.5300
6:18121651:T:TC	acceptor_gain	0.5200
6:18121672:AGC:A	donor_gain	0.5200
6:18121721:CTT:C	donor_gain	0.5200
6:18121722:TTT:T	donor_gain	0.5200
6:18121834:TGCAA:T	donor_loss	0.5200
6:18121835:GCAAC:G	donor_loss	0.5200
6:18121836:CAACC:C	donor_loss	0.5200
6:18121837:AACC:A	donor_loss	0.5200
6:18121839:C:CA	donor_loss	0.5200
6:18122086:A:C	donor_gain	0.5200
6:18122390:G:A	donor_gain	0.5200
6:18121864:T:TA	donor_loss	0.5100
6:18121994:C:CT	acceptor_gain	0.5100
6:18122085:AATGT:A	donor_gain	0.5100
6:18121707:A:AC	donor_gain	0.5000
6:18121708:C:CC	donor_gain	0.5000
6:18121809:C:A	donor_gain	0.5000
6:18121840:C:G	donor_loss	0.5000
6:18121916:C:CT	donor_gain	0.4900
6:18122042:C:CT	donor_gain	0.4900
6:18121723:TTC:T	donor_gain	0.4800
6:18121769:CCAGG:C	donor_gain	0.4800

AlphaMissense

2551 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:18122397:G:C	F70L	0.998
6:18122397:G:T	F70L	0.998
6:18122399:A:G	F70L	0.998
6:18122405:A:G	C68R	0.997
6:18122456:A:G	C51R	0.997
6:18122531:A:G	C26R	0.997
6:18122038:A:T	V190D	0.996
6:18122530:C:G	C26S	0.996
6:18122531:A:T	C26S	0.996
6:18122445:G:C	C54W	0.995
6:18122446:C:T	C54Y	0.995
6:18122447:A:G	C54R	0.995
6:18122454:G:C	C51W	0.995
6:18122455:C:T	C51Y	0.994
6:18122521:C:G	C29S	0.994
6:18122522:A:G	C29R	0.994
6:18122522:A:T	C29S	0.994
6:18122398:A:C	F70C	0.993
6:18122404:C:G	C68S	0.993
6:18122405:A:T	C68S	0.993
6:18122520:G:C	C29W	0.993
6:18122521:C:T	C29Y	0.993
6:18122529:G:C	C26W	0.993
6:18122221:G:T	P129H	0.992
6:18122396:A:G	C71R	0.992
6:18122403:G:C	C68W	0.992
6:18122470:C:T	C46Y	0.992
6:18122530:C:A	C26F	0.992
6:18122530:C:T	C26Y	0.992
6:18122392:C:A	R72M	0.991

dbSNP variants (sampled 300 via entrez): RS1000364203 (6:18120675 T>C), RS1001273192 (6:18123395 C>T), RS1001289855 (6:18121213 G>A), RS1003144524 (6:18121048 T>A), RS1004383948 (6:18120009 C>T), RS1004411446 (6:18120214 G>A), RS1005265727 (6:18121259 G>A,T), RS1005648807 (6:18121268 A>G), RS1005927458 (6:18121026 T>C), RS1006937839 (6:18122136 C>G,T), RS1007514060 (6:18124517 G>A), RS1009188803 (6:18123065 C>T), RS1010334270 (6:18123345 G>T), RS1011115058 (6:18123357 T>C), RS1011706675 (6:18122177 C>T)

Disease associations

OMIM: gene MIM:608072 | disease phenotypes: MIM:254780, MIM:620681

GenCC curated gene-disease

Disease	Classification	Inheritance
Lafora disease	Definitive	Autosomal recessive
myoclonic epilepsy of Lafora 1	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Lafora disease	Definitive	AR

Mondo (3): Lafora disease (MONDO:0009697), myoclonic epilepsy of Lafora 2 (MONDO:0800306), myoclonic epilepsy of Lafora 1 (MONDO:0958199)

Orphanet (1): Lafora disease (Orphanet:501)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000726	Dementia
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001312	Giant somatosensory evoked potentials
HP:0001336	Myoclonus
HP:0001399	Hepatic failure
HP:0002069	Bilateral tonic-clonic seizure
HP:0002100	Recurrent aspiration pneumonia
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure
HP:0002133	Status epilepticus
HP:0002315	Headache
HP:0002344	Progressive neurologic deterioration
HP:0002360	Sleep disturbance
HP:0002367	Visual hallucination
HP:0002384	Focal impaired awareness seizure
HP:0002521	Hypsarrhythmia
HP:0002540	Inability to walk
HP:0003621	Juvenile onset
HP:0007270	Atypical absence seizure
HP:0007334	Bilateral tonic-clonic seizure with focal onset
HP:0007359	Focal-onset seizure

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005287_3	Intrinsic epigenetic age acceleration	4.000000e-25
GCST005287_4	Intrinsic epigenetic age acceleration	2.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0000473	epigenetic status
EFO:0022597	aging

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020192	Lafora Disease	C10.228.140.490.375.130.650.500; C10.228.140.490.493.063.650.500; C10.574.500.529; C16.320.400.480

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12199316	NHLRC1		0.00	0

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
mancozeb	decreases expression	1
chromium hexavalent ion	decreases expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	increases expression, affects cotreatment	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Pantothenic Acid	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases methylation	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_FV44	GM08935	Finite cell line	Male
CVCL_FV45	GM08936	Finite cell line	Male

Clinical trials (associated diseases)

4 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT06609889	PHASE1/PHASE2	RECRUITING	A Safety and Efficacy of Intrathecally Administered ION283 in Patients With Lafora Disease
NCT00007124	Not specified	COMPLETED	Ketogenic Diet in Lafora Disease
NCT03876522	Not specified	COMPLETED	Natural History and Functional Status Study of Patients With Lafora Disease
NCT05930223	Not specified	AVAILABLE	Intravenous VAL-1221 Lafora Expanded Access Protocol