NHLRC1
Chr 6ARNHL repeat containing E3 ubiquitin protein ligase 1
Also known as: EPM2B, MALIN, MELF2, bA204B7.2
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.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
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.
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
0 submitted variants 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.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools