NHLRC1

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

Basic information

Region (hg38): 6:18120439-18122677

Links

ENSG00000187566 ∙ NCBI:378884 ∙ OMIM:608072 ∙ HGNC:21576 ∙ Uniprot:Q6VVB1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Lafora disease (Strong), mode of inheritance: AR
• Lafora disease (Definitive), mode of inheritance: AR
• Lafora disease (Strong), mode of inheritance: AR
• Lafora disease (Strong), mode of inheritance: AR
• Lafora disease (Supportive), mode of inheritance: AR
• Lafora disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epilepsy, progressive myoclonic 2B (Lafora)	AR	General	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	Neurologic	10513696; 14663053; 12958597; 15781812; 16021330; 16356781; 16950819; 19267391; 20301563
While antiepileptic drugs may be effective, certain medications (eg, phenytoin, and possibly carbamazepine, oxcarbazepine, and lamotrigine) can exacerbate myoclonus

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NHLRC1 gene.

• Lafora disease (299 variants)
• not provided (67 variants)
• Inborn genetic diseases (46 variants)
• not specified (19 variants)
• Epilepsy, progressive myoclonic, 2b (4 variants)
• Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NHLRC1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	72	3	80
missense	3	9	167	1	1	181
nonsense	4	3				7
start loss						0
frameshift	13	3	1			17
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			18	7	9	34
Total	20	15	193	80	13

Highest pathogenic variant AF is 0.0000788

Variants in NHLRC1

This is a list of pathogenic ClinVar variants found in the NHLRC1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-18120533-C-T		Lafora disease	Benign (Apr 27, 2017)
6-18120544-A-G		Lafora disease	Likely benign (Jan 12, 2018)
6-18120544-A-T		Lafora disease	Uncertain significance (Jan 13, 2018)
6-18120582-C-T		Lafora disease	Uncertain significance (Jan 12, 2018)
6-18120622-T-C		Lafora disease	Uncertain significance (Jan 13, 2018)
6-18120699-A-G		Lafora disease	Likely benign (Jan 13, 2018)
6-18120757-G-C		Lafora disease	Uncertain significance (Jan 12, 2018)
6-18120793-G-A		Lafora disease	Benign (Jan 13, 2018)
6-18120798-A-T		Lafora disease	Benign (Jan 13, 2018)
6-18120882-A-G		Lafora disease	Uncertain significance (Apr 27, 2017)
6-18120937-G-C		Lafora disease	Benign (Jan 12, 2018)
6-18120977-C-G		Lafora disease	Uncertain significance (Jan 13, 2018)
6-18121013-T-C		Lafora disease	Uncertain significance (Jan 13, 2018)
6-18121057-CTACT-C		Lafora disease	Uncertain significance (Jun 14, 2016)
6-18121075-T-A		Lafora disease	Benign/Likely benign (Jul 15, 2018)
6-18121083-C-T		Lafora disease	Benign (Jun 14, 2018)
6-18121087-C-A		Lafora disease	Uncertain significance (Jan 12, 2018)
6-18121092-C-G		Lafora disease	Uncertain significance (Jan 13, 2018)
6-18121093-G-A		Lafora disease	Uncertain significance (Jan 13, 2018)
6-18121099-C-T		Lafora disease	Likely benign (Jul 26, 2018)
6-18121143-C-G		Lafora disease	Benign/Likely benign (Jul 07, 2018)
6-18121171-G-C		Lafora disease	Uncertain significance (Jan 13, 2018)
6-18121171-G-T		Lafora disease	Uncertain significance (Jan 13, 2018)
6-18121182-A-G		Lafora disease	Benign/Likely benign (Jun 14, 2018)
6-18121209-A-G		Lafora disease	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NHLRC1	protein_coding	protein_coding	ENST00000340650	1	2134

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0943	0.872	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.495	219	241	0.910	0.0000140	2521
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: Ubiquitin mediated proteolysis - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.183

Intolerance Scores

• loftool: 0.186
• rvis_EVS: 0.22
• rvis_percentile_EVS: 68.13

Haploinsufficiency Scores

• pHI: 0.241
• hipred: Y
• hipred_score: 0.775
• ghis: 0.474

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.916

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nhlrc1
• Phenotype: pigmentation phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype

Gene ontology

• Biological process: protein polyubiquitination;glycogen biosynthetic process;autophagy;positive regulation of protein ubiquitination;proteasome-mediated ubiquitin-dependent protein catabolic process
• Cellular component: nucleus;endoplasmic reticulum;cytosol;perinuclear region of cytoplasm
• Molecular function: ubiquitin-protein transferase activity;protein binding;metal ion binding;ubiquitin protein ligase activity