NHLRC1

protein-coding

NHL repeat containing E3 ubiquitin protein ligase 1, the group of Ring finger proteins

Gene summary

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).[provided by RefSeq, Mar 2010]

MANE transcript

NM_198586.3

Inheritance

ClinVar variants

P:52U:193B:98

Top phenotype

Myoclonic epilepsy of Lafora 2

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr6:18,120,440-18,122,677

External References & Databases

Ensembl (ENSG00000187566)

Transcript & Mutation Effects

hg38 • Region Span ~2.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myoclonic epilepsy of Lafora 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0958199

Submitter: PanelApp Australia

Lafora diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: Labcorp Genetics (formerly Invitae)

Lafora diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: Ambry Genetics

Lafora diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: Orphanet

Lafora diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: Genomics England PanelApp

Lafora diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009697

Submitter: ClinGen

NHLRC1 was first reported in relation to autosomal recessive Lafora disease in 2003 (Chan et al., PMID: 12958597 and PMID: 12960212). At least 85 unique variants (e.g. missense, nonsense, frameshift, deletion, etc.) have been reported in humans (see http://projects.tcag.ca/lafora). Evidence supporting this gene-disease relationship includes case-level data and experimental data. The mechanism for disease is homozygous loss of function (PMID: 21505799). This gene has not been implicated in any other disease associations. GENETIC EVIDENCE: Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 21 probands in 7 publications (PMIDs: 16190947, 12958597, 16529633, 15781812, 22047982, 18256682, 18263761). Variants in this gene segregated with disease in at least 38 additional family members. Of note, the presence of Lafora bodies by biopsy or on autopsy was considered supporting evidence for the function effect of non-null variants. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. EXPERIMENTAL EVIDENCE This gene-disease association is supported by (animal models and in vitro functional assays, etc.) In summary, NHLRC1 is definitively associated with autosomal recessive Lafora disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time This classification was approved by the ClinGen Epilepsy Working Group on 3/3/2020 using (SOP Version 7).

Clinical Genomic Database (CGD)

Myoclonic epilepsy of Lafora 2AR

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

Refs: 10513696; 14663053; 12958597; 15781812; 16021330; 16356781; 16950819; 19267391; 20301563

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NHLRC1 variants in ClinVar

7 Conditions Cataloged

Lafora diseaseTotal: 288

not providedTotal: 83

Inborn genetic diseasesTotal: 73

not specifiedTotal: 24

Myoclonic epilepsy of Lafora 2Total: 18

NHLRC1-related disorderTotal: 9

Myoclonic epilepsy of Lafora 1Total: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198586.3. 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			7 clinvar	85 clinvar	2 clinvar	94
missense	5 clinvar	13 clinvar	185 clinvar	10 clinvar	1 clinvar	214
nonsense	6 clinvar	3 clinvar				9
start loss						0
frameshift	20 clinvar	5 clinvar	1 clinvar			26
splice donor/acceptor (+/-2bp)						0
Total	31	21	193	95	3	343

Highest pathogenic variant AF is 0.00012305929

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_198586.3	RefSeq	NP_940988.2	1	MANE Select
ENST00000340650.6	Ensembl	ENSP00000345464.3	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)

Biological Process

protein polyubiquitination
glycogen biosynthetic process
autophagy
positive regulation of protein ubiquitination
proteasome-mediated ubiquitin-dependent protein catabolic process

Molecular Function

ubiquitin-protein transferase activity
protein binding
metal ion binding
ubiquitin protein ligase activity

Cellular Component

nucleus
endoplasmic reticulum
cytosol
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000340650
Coding exons: 1
Length: 2134
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.495	219	241	0.910	0.0000140	2521
Missense (PolyPhen)		62	70.922	0.8742		737
Synonymous	-0.341	112	108	1.04	0.00000705	878
Loss of Function	1.82	3	8.83	0.340	5.09e-7	89

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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. {ECO:0000269|PubMed:15930137, ECO:0000269|PubMed:17908927, ECO:0000269|PubMed:18070875, ECO:0000269|PubMed:19036738, ECO:0000269|PubMed:21505799, ECO:0000269|PubMed:23624058}.;
Disease: DISEASE: Epilepsy, progressive myoclonic 2 (EPM2) [MIM:254780]: An autosomal recessive and severe form of adolescent-onset progressive epilepsy. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. EPM2 occurs worldwide, but it is particularly common in the mediterranean countries of southern Europe and northern Africa, in southern India and in the Middle East. At the cellular level, it 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. Among other conditions involving polyglucosans, EPM2 is unique in that the inclusions are in neuronal dendrites but not axons and the forming polyglucosan fibrils are associated with the endoplasmic reticulum. {ECO:0000269|PubMed:12958597, ECO:0000269|PubMed:15781812, ECO:0000269|PubMed:15930137, ECO:0000269|PubMed:16021330, ECO:0000269|PubMed:18311786, ECO:0000269|PubMed:21505799}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.183

Intolerance Scores

LoFtool: 0.186
RVIS EVS: 0.22
RVIS percentile EVS: 68.13

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.916

Gene Damage Prediction

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