NHLRC1

Chr 6AR

NHL repeat containing E3 ubiquitin protein ligase 1

Also known as: EPM2B, MALIN, MELF2, bA204B7.2

NCBI Gene: 378884 ENSG00000187566 UniProt: Q6VVB1 OMIM: 608072

This gene encodes an E3 ubiquitin-protein ligase that works with laforin phosphatase to clear toxic polyglucosan and protein aggregates through both the ubiquitin-proteasome system and autophagy pathways. Biallelic mutations cause Lafora disease (progressive myoclonic epilepsy type 2), a devastating autosomal recessive neurodegenerative disorder typically presenting in adolescence with progressive myoclonic epilepsy and cognitive decline.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.881 OMIM phenotype

Clinical Summary— NHLRC1

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Gene-Disease Validity (ClinGen)

Lafora disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

51 unique Pathogenic / Likely Pathogenic· 211 VUS of 381 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NHLRC1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.094

Z-score 1.82

OE 0.34 (0.15–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.50Z-score

OE missense 0.91 (0.81–1.02)

219 obs / 240.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.15–0.88)

0≤0.351.4

Missense OE?0.91 (0.81–1.02)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 3 / 8.8Missense obs/exp: 219 / 240.6Syn Z: -0.34

This gene — mechanism propensity

0.6455th %ile

GOF

0.6637th %ile

LOF

0.3649th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

381 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32

Likely Pathogenic19

VUS211

Likely Benign90

Benign13

Conflicting16

Pathogenic

Likely Pathogenic

211

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	26	5	1	0	32
Likely Pathogenic	7	12	0	0	19
VUS	1	187	17	6	211
Likely Benign	0	1	9	80	90
Benign	0	1	10	2	13
Conflicting	—				16
Total	34	206	37	88	381

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap NHLRC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →