DNM1

Chr 9ADAR

dynamin 1

Also known as: DEE31, DEE31A, DEE31B, DNM, EIEE31

NCBI Gene: 1759 ENSG00000106976 UniProt: Q05193 OMIM: 602377

The protein tubulates and severs membranes through its mechanochemical GTPase activity and is essential for clathrin-mediated endocytosis and vesicular trafficking processes. Mutations cause developmental and epileptic encephalopathy 31A (autosomal dominant) and 31B (autosomal recessive), with the gene being highly intolerant to loss-of-function variants. Disease can result from different mechanisms depending on the specific variant, with some mutations likely causing haploinsufficiency while others may act through dominant-negative or gain-of-function effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.252 OMIM phenotypes

Clinical Summary— DNM1

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Gene-Disease Validity (ClinGen)

developmental and epileptic encephalopathy · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.25LOEUF

pLI 0.999

Z-score 5.54

OE 0.13 (0.07–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

5.18Z-score

OE missense 0.35 (0.31–0.40)

181 obs / 510.2 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios

LoF OE0.13 (0.07–0.25)

0≤0.351.4

Missense OE0.35 (0.31–0.40)

0≤0.61.4

Synonymous OE0.85

0≤1.21.6

LoF obs/exp: 6 / 47.0Missense obs/exp: 181 / 510.2Syn Z: 1.67

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateDNM1-related microcephaly, developmental and epileptic encephalopathy (biallelic)LOFAR

strongDNM1-related microcephaly, developmental and epileptic encephalopathy (monoallelic)DNAD

0.5674th %ile

GOF

0.4875th %ile

LOF

0.62top 25%

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

LOFLOEUF 0.25

DN1 literature citation

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.

Literature Evidence

DNAll mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.PMID:28667181

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.