NHLRC1

Chr 6AR

NHL repeat containing E3 ubiquitin protein ligase 1

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

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]

OMIMResearchGenerating clinical summary…
MultiplemechanismARLOEUF 0.881 OMIM phenotype
Clinical SummaryNHLRC1
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Gene-Disease Validity (ClinGen)
Lafora disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?
0.88LOEUF
pLI 0.094
Z-score 1.82
OE 0.34 (0.150.88)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
0.50Z-score
OE missense 0.91 (0.811.02)
219 obs / 240.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.34 (0.150.88)
00.351.4
Missense OE?0.91 (0.811.02)
00.61.4
Synonymous OE?1.04
01.21.6
LoF obs/exp: 3 / 8.8Missense obs/exp: 219 / 240.6Syn Z: -0.34

This gene — mechanism propensity

DN
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

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.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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