DNM1L

dynamin 1 like

Basic information

Region (hg38): 12:32679199-32745650

Links

ENSG00000087470 ∙ NCBI:10059 ∙ OMIM:603850 ∙ HGNC:2973 ∙ Uniprot:O00429 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant optic atrophy, classic form (Supportive), mode of inheritance: AD
• encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (Supportive), mode of inheritance: AD
• encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (Strong), mode of inheritance: AR
• encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (Moderate), mode of inheritance: AR
• optic atrophy 5 (Strong), mode of inheritance: AD
• encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (Strong), mode of inheritance: AD
• Leigh syndrome (Limited), mode of inheritance: AR
• encephalopathy due to mitochondrial and peroxisomal fission defect (Definitive), mode of inheritance: AD
• Leigh syndrome (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Encephalopathy due to defective mitochondrial and peroxisomal fission 1; Optic atrophy 5	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Biochemical; Neurologic; Ophthalmologic	15635063; 17460227; 28969390

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DNM1L gene.

• not provided (510 variants)
• not specified (40 variants)
• Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (38 variants)
• Inborn genetic diseases (17 variants)
• Lethal Encephalopathy (16 variants)
• Myopathy, lactic acidosis, and sideroblastic anemia (11 variants)
• Hereditary Sideroblastic Anemia with Myopathy and Lactic Acidosis (11 variants)
• Optic atrophy 5 (7 variants)
• Optic atrophy 5;Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (5 variants)
• Mitochondrial disease (4 variants)
• Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1;Optic atrophy 5 (3 variants)
• DNM1L-related disorders (2 variants)
• See cases (2 variants)
• Obesity (1 variants)
• DNM1L-related movement disorder (1 variants)
• Hereditary spastic paraplegia 8 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DNM1L gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	105	4	113
missense	5	20	154	1		180
nonsense	2	2	1			5
start loss						0
frameshift	7	1				8
inframe indel		1	6			7
splice donor/acceptor (+/-2bp)		5		1		6
splice region			17	29	2	48
non coding			7	129	54	190
Total	14	29	172	236	58

Highest pathogenic variant AF is 0.0000197

Variants in DNM1L

This is a list of pathogenic ClinVar variants found in the DNM1L region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-32679316-A-G		not specified	Likely benign (Feb 03, 2016)
12-32679332-G-T		not specified	Benign (Dec 26, 2013)
12-32679339-A-G		not specified	Likely benign (Sep 30, 2016)
12-32679346-C-T			Likely benign (Oct 15, 2020)
12-32679350-G-A		not specified	Benign (Jan 23, 2015)
12-32679368-A-C		Optic atrophy 5	Pathogenic (Nov 08, 2017)
12-32679370-G-A			Uncertain significance (Mar 20, 2023)
12-32679372-G-C			Likely benign (Jul 17, 2023)
12-32679373-C-A			Uncertain significance (Nov 08, 2023)
12-32679373-C-G			Uncertain significance (Dec 13, 2023)
12-32679385-A-C			Uncertain significance (Jan 17, 2024)
12-32679388-A-C		Inborn genetic diseases	Uncertain significance (Jan 19, 2024)
12-32679388-AACA-CACT		Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1	Conflicting classifications of pathogenicity (Sep 26, 2023)
12-32679391-A-T		Obesity	Pathogenic (Jan 19, 2024)
12-32679392-A-G			Uncertain significance (Aug 04, 2023)
12-32679400-G-A			Uncertain significance (Apr 17, 2023)
12-32679414-G-T			Likely benign (Aug 16, 2022)
12-32679418-G-A			Uncertain significance (Jul 25, 2023)
12-32679420-C-T			Likely benign (Jan 04, 2024)
12-32679429-C-T			Likely benign (Jan 07, 2022)
12-32679436-C-T			Likely benign (Aug 12, 2022)
12-32679439-C-A			Uncertain significance (May 31, 2022)
12-32679444-A-C			Uncertain significance (Sep 27, 2022)
12-32679453-A-C			Likely benign (Nov 27, 2023)
12-32679458-G-C			Likely pathogenic (Jul 28, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DNM1L	protein_coding	protein_coding	ENST00000549701	20	66353

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000568	0.999	125706	0	42	125748	0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.83	187	403	0.464	0.0000211	4796
Missense in Polyphen		47	144.11	0.32613		1719
Synonymous	0.263	133	137	0.971	0.00000685	1453
Loss of Function	4.13	14	43.3	0.323	0.00000246	504

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000508	0.000503
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000167	0.000167
Middle Eastern	0.0000544	0.0000544
South Asian	0.000131	0.000131
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Functions in mitochondrial and peroxisomal division. Mediates membrane fission through oligomerization into membrane- associated tubular structures that wrap around the scission site to constrict and sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism. Through its function in mitochondrial division, ensures the survival of at least some types of postmitotic neurons, including Purkinje cells, by suppressing oxidative damage. Required for normal brain development, including that of cerebellum. Facilitates developmentally regulated apoptosis during neural tube formation. Required for a normal rate of cytochrome c release and caspase activation during apoptosis; this requirement may depend upon the cell type and the physiological apoptotic cues. Plays an important role in mitochondrial fission during mitosis (PubMed:26992161, PubMed:27301544, PubMed:27328748). Required for formation of endocytic vesicles. Proposed to regulate synaptic vesicle membrane dynamics through association with BCL2L1 isoform Bcl-X(L) which stimulates its GTPase activity in synaptic vesicles; the function may require its recruitment by MFF to clathrin-containing vesicles. Required for programmed necrosis execution. {ECO:0000269|PubMed:11514614, ECO:0000269|PubMed:12499366, ECO:0000269|PubMed:17015472, ECO:0000269|PubMed:17301055, ECO:0000269|PubMed:17460227, ECO:0000269|PubMed:17553808, ECO:0000269|PubMed:18695047, ECO:0000269|PubMed:18838687, ECO:0000269|PubMed:19342591, ECO:0000269|PubMed:19411255, ECO:0000269|PubMed:19638400, ECO:0000269|PubMed:20688057, ECO:0000269|PubMed:23283981, ECO:0000269|PubMed:23530241, ECO:0000269|PubMed:23584531, ECO:0000269|PubMed:23921378, ECO:0000269|PubMed:26992161, ECO:0000269|PubMed:27145208, ECO:0000269|PubMed:27301544, ECO:0000269|PubMed:27328748, ECO:0000269|PubMed:9570752, ECO:0000269|PubMed:9786947}.; FUNCTION: Isoform 4: Inhibits peroxisomal division when overexpressed. {ECO:0000269|PubMed:12618434}.
• Disease: DISEASE: Note=May be associated with Alzheimer disease through amyloid-beta-induced increased S-nitrosylation of DNM1L, which triggers, directly or indirectly, excessive mitochondrial fission, synaptic loss and neuronal damage. {ECO:0000269|PubMed:19342591}.; DISEASE: Encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1) [MIM:614388]: A rare autosomal dominant systemic disorder resulting in lack of neurologic development and death in infancy. After birth, infants present in the first week of life with poor feeding and neurologic impairment, including hypotonia, little spontaneous movement, no tendon reflexes, no response to light stimulation, and poor visual fixation. Other features include mildly elevated plasma concentration of very-long-chain fatty acids, lactic acidosis, microcephaly, deep-set eyes, optic atrophy and hypoplasia, and an abnormal gyral pattern in both frontal lobes associated with dysmyelination. {ECO:0000269|PubMed:17460227, ECO:0000269|PubMed:26604000, ECO:0000269|PubMed:26992161, ECO:0000269|PubMed:27145208, ECO:0000269|PubMed:27301544, ECO:0000269|PubMed:27328748}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Optic atrophy 5 (OPA5) [MIM:610708]: A form of optic atrophy, a disease characterized by progressive visual loss in association with a deficiency in the number of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. OPA5 is an autosomal dominant non-syndromic form that manifests as slowly progressive visual loss with variable onset from the first to third decades. Additional ocular abnormalities may include central scotoma and dyschromatopsia. {ECO:0000269|PubMed:28969390}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: TNF signaling pathway - Homo sapiens (human);Necroptosis - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Synaptic Vesicle Pathway;Apoptotic execution phase;Apoptosis;Programmed Cell Death (Consensus)

Recessive Scores

• pRec: 0.250

Intolerance Scores

• loftool: 0.129
• rvis_EVS: -0.98
• rvis_percentile_EVS: 8.75

Haploinsufficiency Scores

• pHI: 0.407
• hipred: Y
• hipred_score: 0.736
• ghis: 0.711

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Dnm1l
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); muscle phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; embryo phenotype; skeleton phenotype; vision/eye phenotype

Gene ontology

• Biological process: mitochondrial fission;release of cytochrome c from mitochondria;dynamin family protein polymerization involved in mitochondrial fission;mitochondrion organization;endoplasmic reticulum organization;apoptotic mitochondrial changes;negative regulation of mitochondrial fusion;regulation of mitochondrion organization;peroxisome fission;regulation of protein oligomerization;synaptic vesicle recycling via endosome;positive regulation of apoptotic process;positive regulation of GTPase activity;mitochondrial fragmentation involved in apoptotic process;intracellular distribution of mitochondria;synaptic vesicle endocytosis;positive regulation of protein secretion;protein complex oligomerization;protein homotetramerization;heart contraction;positive regulation of dendritic spine morphogenesis;membrane fusion;necroptotic process;mitochondrion morphogenesis;protein localization to mitochondrion;positive regulation of mitochondrial fission;mitochondrial membrane fission;positive regulation of release of cytochrome c from mitochondria;cellular response to oxygen-glucose deprivation;execution phase of apoptosis;regulation of peroxisome organization;positive regulation of synaptic vesicle endocytosis;regulation of autophagy of mitochondrion;regulation of ATP metabolic process;cellular response to thapsigargin;response to flavonoid;response to hypobaric hypoxia;positive regulation of synaptic vesicle exocytosis;positive regulation of intrinsic apoptotic signaling pathway
• Cellular component: Golgi membrane;cytoplasm;mitochondrion;mitochondrial outer membrane;peroxisome;endoplasmic reticulum;endoplasmic reticulum membrane;Golgi apparatus;cytosol;microtubule;brush border;clathrin-coated pit;membrane;cell junction;synaptic vesicle membrane;mitochondrial membrane;protein-containing complex;intracellular membrane-bounded organelle;perinuclear region of cytoplasm;postsynapse;presynaptic endocytic zone membrane;mitochondrion-derived vesicle
• Molecular function: GTPase activity;GTPase activator activity;protein binding;GTP binding;microtubule binding;lipid binding;Rab GTPase binding;clathrin binding;GTP-dependent protein binding;ubiquitin protein ligase binding;protein homodimerization activity;protein-containing complex binding;BH2 domain binding