NHLRC1

Chr 6AR

NHL repeat containing E3 ubiquitin protein ligase 1

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

NCBI Gene: 378884ENSG00000187566UniProt: Q6VVB1

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]

Primary Disease Associations & Inheritance

Myoclonic epilepsy of Lafora 2MIM #620681
AR
397
ClinVar variants
64
Pathogenic / LP
0.09
pLI score
0
Active trials
Clinical Summary— NHLRC1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
64 Pathogenic / Likely Pathogenic· 214 VUS of 397 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.88LOEUF
pLI 0.094
Z-score 1.82
OE 0.34 (0.15–0.88)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.50Z-score
OE missense 0.91 (0.81–1.02)
219 obs / 240.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.34 (0.15–0.88)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.81–1.02)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 3 / 8.8Missense obs/exp: 219 / 240.6Syn Z: -0.34

ClinVar Variant Classifications

397 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46
Likely Pathogenic18
VUS214
Likely Benign90
Benign13
Conflicting16
46
Pathogenic
18
Likely Pathogenic
214
VUS
90
Likely Benign
13
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
5
23
0
46
Likely Pathogenic
3
12
3
0
18
VUS
1
184
23
6
214
Likely Benign
0
1
9
80
90
Benign
0
1
10
2
13
Conflicting
—16
Total222036888397

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

View in ClinVar →

Protein Context — Lollipop Plot

NHLRC1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Myoclonic epilepsy of Lafora 2

MIM #620681

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Polyglucosan storage myopathies.
Hedberg-Oldfors C et al.·Mol Aspects Med
2015Review
Multi-omic underpinnings of epigenetic aging and human longevity.
Mavromatis LA et al.·Nat Commun
2023
Lafora disease: severe phenotype associated with homozygous deletion of the NHLRC1 gene.
Kecmanović M et al.·J Neurol Sci
2013Review
Lafora progressive myoclonus epilepsy: a meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes.
Singh S et al.·Hum Mutat
2009Review
Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy.
Singh S et al.·J Med Genet
2006Cohort
The rare rs769301934 variant in NHLRC1 is a common cause of Lafora disease in Turkey.
Haryanyan G et al.·J Hum Genet
2021
Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data.
Pondrelli F et al.·Orphanet J Rare Dis
2023Meta-analysis
Lafora disease: from genotype to phenotype.
Parihar R et al.·J Genet
2018Review
Lafora disease in the Indian population: EPM2A and NHLRC1 gene mutations and their impact on subcellular localization of laforin and malin.
Singh S et al.·Hum Mutat
2008
Lafora disease - from pathogenesis to treatment strategies.
Nitschke F et al.·Nat Rev Neurol
2018Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools