DYNC1H1

dynein cytoplasmic 1 heavy chain 1, the group of Dynein 1 complex subunits

Basic information

Region (hg38): 14:101964572-102056443

Previous symbols: [ "DNECL", "DNCL", "DNCH1" ]

Links

ENSG00000197102 ∙ NCBI:1778 ∙ OMIM:600112 ∙ HGNC:2961 ∙ Uniprot:Q14204 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (Definitive), mode of inheritance: AD
• autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (Strong), mode of inheritance: AD
• intellectual disability, autosomal dominant 13 (Strong), mode of inheritance: AD
• intellectual disability, autosomal dominant 13 (Definitive), mode of inheritance: AD
• autosomal dominant non-syndromic intellectual disability (Supportive), mode of inheritance: AD
• autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease axonal type 2O (Supportive), mode of inheritance: AD
• intellectual disability, autosomal dominant 13 (Strong), mode of inheritance: AD
• Charcot-Marie-Tooth disease axonal type 2O (Strong), mode of inheritance: AD
• neuronopathy, distal hereditary motor (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, axonal, type 2O; Intellectual developmental disorder, autosomal dominant 13; Cortical dysplasia, complex, with other brain malformations 13; Spinal muscular atrophy, lower extremity-predominant 1, autosomal dominant	AD	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	Craniofacial; Musculoskeletal; Neurologic	20697106; 21076407; 21820100; 22459677; 22368300; 25140959

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DYNC1H1 gene.

• Charcot-Marie-Tooth disease axonal type 2O (3099 variants)
• not provided (1096 variants)
• Inborn genetic diseases (526 variants)
• not specified (289 variants)
• Autosomal dominant cerebellar ataxia (179 variants)
• Charcot-Marie-Tooth disease (174 variants)
• Intellectual disability, autosomal dominant 13 (120 variants)
• Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (37 variants)
• DYNC1H1-related condition (32 variants)
• Intellectual disability (17 variants)
• Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures;Intellectual disability, autosomal dominant 13;Charcot-Marie-Tooth disease axonal type 2O (15 variants)
• Intellectual disability, autosomal dominant 13;Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures;Charcot-Marie-Tooth disease axonal type 2O (13 variants)
• Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures;Charcot-Marie-Tooth disease axonal type 2O;Intellectual disability, autosomal dominant 13 (11 variants)
• Lissencephaly (10 variants)
• Neuronopathy, distal hereditary motor, autosomal dominant (8 variants)
• Autism spectrum disorder (7 variants)
• See cases (6 variants)
• DYNC1H1-related neurodevelopmental disorders (6 variants)
• Charcot-Marie-Tooth disease axonal type 2O;Intellectual disability, autosomal dominant 13;Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (6 variants)
• Intellectual disability, autosomal dominant 13;Charcot-Marie-Tooth disease axonal type 2O;Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (5 variants)
• Distal spinal muscular atrophy (4 variants)
• DYNC1H1-related neuronopathy (3 variants)
• Arthrogryposis multiplex congenita;Fetal akinesia deformation sequence 1 (2 variants)
• Charcot-Marie-Tooth disease axonal type 2O;Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures;Intellectual disability, autosomal dominant 13 (2 variants)
• Spinal muscular atrophy with lower extremity predominance (2 variants)
• Intellectual Disability, Dominant (2 variants)
• Charcot-Marie-Tooth disease type 2 (2 variants)
• Neurodevelopmental delay (2 variants)
• Charcot-Marie-Tooth disease, type I (2 variants)
• DYNC1H1-related disorders (2 variants)
• 7 conditions (1 variants)
• Abnormality of neuronal migration (1 variants)
• Distal lower limb muscle weakness (1 variants)
• Muscle weakness;Myopathy (1 variants)
• Polyneuropathy (1 variants)
• Microcephaly;Infantile spasms;Pachygyria;Global developmental delay;Hypoplasia of the corpus callosum (1 variants)
• Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures;Spinal muscular atrophy with lower extremity predominance;Charcot-Marie-Tooth disease axonal type 2O (1 variants)
• Seizure (1 variants)
• Progressive muscle weakness (1 variants)
• Distal lower limb amyotrophy;Pes cavus;Hammertoe;Myopathy (1 variants)
• Intellectual disability, autosomal dominant 13;Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (1 variants)
• Corpus callosum, agenesis of;Ectopic tissue;Seizure;Focal-onset seizure (1 variants)
• Charcot-Marie-Tooth disease axonal type 2O;Intellectual disability, autosomal dominant 13;Spinal muscular atrophy with lower extremity predominance (1 variants)
• Charcot-Marie-Tooth disease type 5 (1 variants)
• Charcot-Marie-Tooth disease type 4 (1 variants)
• Lower limb muscle weakness (1 variants)
• Global developmental delay (1 variants)
• Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures;Charcot-Marie-Tooth disease axonal type 2O (1 variants)
• Neurodevelopmental disorder (1 variants)
• Peripheral neuropathy (1 variants)
• Spinal muscular atrophy (1 variants)
• DYNC1H1-Related Disorder (1 variants)
• Abnormality of the nervous system (1 variants)
• Global developmental delay;Microcephaly;Delayed gross motor development;Delayed speech and language development;Seizure (1 variants)
• 9 conditions (1 variants)
• Hereditary motor and sensory neuropathy (1 variants)
• Intellectual disability;Seizure (1 variants)
• Neurodevelopmental abnormality (1 variants)
• Charcot-Marie-Tooth disease axonal type 2O;Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DYNC1H1 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			39	1053	24	1116
missense	25	85	1212	184	9	1515
nonsense		2	25			27
start loss						0
frameshift		2	37			39
inframe indel		5	19			24
splice donor/acceptor (+/-2bp)		4	17	2		23
splice region		1	105	141	4	251
non coding		1	24	497	157	679
Total	25	99	1373	1736	190

Variants in DYNC1H1

This is a list of pathogenic ClinVar variants found in the DYNC1H1 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-101964602-C-T		Charcot-Marie-Tooth disease axonal type 2O • Autosomal dominant cerebellar ataxia	Uncertain significance (Jan 13, 2018)
14-101964639-G-A		Charcot-Marie-Tooth disease axonal type 2O • Autosomal dominant cerebellar ataxia	Benign (Jan 13, 2018)
14-101964645-T-A			Benign (Nov 24, 2020)
14-101964679-C-G		Charcot-Marie-Tooth disease axonal type 2O • Autosomal dominant cerebellar ataxia • not specified • DYNC1H1-related disorder	Likely benign (Nov 11, 2022)
14-101964687-A-G		Autosomal dominant cerebellar ataxia • Charcot-Marie-Tooth disease axonal type 2O • Charcot-Marie-Tooth disease • not specified • Inborn genetic diseases	Benign (Oct 14, 2023)
14-101964689-A-G		Inborn genetic diseases	Conflicting classifications of pathogenicity (Nov 08, 2020)
14-101964700-G-A		Charcot-Marie-Tooth disease axonal type 2O	Likely benign (Mar 23, 2023)
14-101964702-C-T		Charcot-Marie-Tooth disease axonal type 2O	Uncertain significance (Jul 17, 2023)
14-101964703-C-T		Charcot-Marie-Tooth disease axonal type 2O	Likely benign (Oct 09, 2023)
14-101964706-G-A		Charcot-Marie-Tooth disease axonal type 2O	Likely benign (Jan 03, 2024)
14-101964706-G-GGGT		Charcot-Marie-Tooth disease axonal type 2O	Uncertain significance (Jan 17, 2024)
14-101964706-G-GGGCGGC			Uncertain significance (Mar 25, 2023)
14-101964708-G-C		Charcot-Marie-Tooth disease axonal type 2O	Uncertain significance (Mar 09, 2020)
14-101964710-G-T		Intellectual disability, autosomal dominant 13	Likely benign (May 06, 2021)
14-101964712-C-T		Charcot-Marie-Tooth disease axonal type 2O	Likely benign (Dec 29, 2021)
14-101964713-G-A		Charcot-Marie-Tooth disease axonal type 2O	Likely benign (Jan 15, 2024)
14-101964715-C-T		Charcot-Marie-Tooth disease axonal type 2O	Likely benign (Apr 30, 2023)
14-101964716-G-A		Charcot-Marie-Tooth disease axonal type 2O	Uncertain significance (Sep 08, 2002)
14-101964717-G-A		Charcot-Marie-Tooth disease axonal type 2O	Uncertain significance (Oct 13, 2022)
14-101964725-G-C		Charcot-Marie-Tooth disease axonal type 2O	Uncertain significance (Feb 11, 2021)
14-101964727-C-G		Charcot-Marie-Tooth disease axonal type 2O • Inborn genetic diseases • DYNC1H1-related disorder	Likely benign (Aug 29, 2022)
14-101964729-C-T		Charcot-Marie-Tooth disease axonal type 2O • Inborn genetic diseases	Likely benign (Dec 16, 2023)
14-101964730-G-C		Charcot-Marie-Tooth disease axonal type 2O	Likely benign (Nov 27, 2020)
14-101964736-A-C		Charcot-Marie-Tooth disease axonal type 2O	Likely benign (May 21, 2022)
14-101964737-T-C		not specified • Autosomal dominant cerebellar ataxia • Charcot-Marie-Tooth disease axonal type 2O • Charcot-Marie-Tooth disease • Inborn genetic diseases	Benign (Feb 01, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DYNC1H1	protein_coding	protein_coding	ENST00000360184	78	86265

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.23e-29	125723	0	25	125748	0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	11.0	1022	2.59e+3	0.394	0.000172	30630
Missense in Polyphen		187	1008.9	0.18534		12005
Synonymous	-1.72	1111	1.04e+3	1.07	0.0000735	8991
Loss of Function	13.3	11	228	0.0482	0.0000126	2670

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000239	0.000239
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.000141	0.000139
European (Non-Finnish)	0.000106	0.000105
Middle Eastern	0.000163	0.000163
South Asian	0.0000653	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Plays a role in mitotic spindle assembly and metaphase plate congression (PubMed:27462074). {ECO:0000269|PubMed:27462074}.
• Disease: DISEASE: Charcot-Marie-Tooth disease 2O (CMT2O) [MIM:614228]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:21820100, ECO:0000269|PubMed:24307404, ECO:0000269|PubMed:25512093}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, autosomal dominant 13 (MRD13) [MIM:614563]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD13 is associated with variable neuronal migration defects and mild dysmorphic features. Some patients may also show signs of peripheral neuropathy, such as abnormal gait and hyporeflexia. {ECO:0000269|PubMed:21076407, ECO:0000269|PubMed:22368300, ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23603762, ECO:0000269|PubMed:28193117}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinal muscular atrophy, lower extremity-predominant 1, autosomal dominant (SMALED1) [MIM:158600]: A form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMALED1 is characterized by muscle weakness predominantly affecting the proximal lower extremities. {ECO:0000269|PubMed:22459677, ECO:0000269|PubMed:22847149, ECO:0000269|PubMed:25484024, ECO:0000269|PubMed:25512093, ECO:0000269|PubMed:26846447, ECO:0000269|PubMed:28193117}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Salmonella infection - Homo sapiens (human);Phagosome - Homo sapiens (human);Vasopressin-regulated water reabsorption - Homo sapiens (human);Neutrophil degranulation;Signal Transduction;Vesicle-mediated transport;Membrane Trafficking;Post-translational protein modification;Metabolism of proteins;Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal;Amplification of signal from the kinetochores;Mitotic Spindle Checkpoint;Cell Cycle Checkpoints;Innate Immune System;Immune System;RHO GTPases Activate Formins;RHO GTPase Effectors;Signaling by Rho GTPases;Regulation of PLK1 Activity at G2/M Transition;Transport to the Golgi and subsequent modification;Asparagine N-linked glycosylation;Recruitment of mitotic centrosome proteins and complexes;Loss of Nlp from mitotic centrosomes;Loss of proteins required for interphase microtubule organization from the centrosome;Centrosome maturation;AURKA Activation by TPX2;G2/M Transition;Mitotic G2-G2/M phases;COPI-independent Golgi-to-ER retrograde traffic;Golgi-to-ER retrograde transport;Recruitment of NuMA to mitotic centrosomes;Mitotic Prometaphase;COPI-mediated anterograde transport;Separation of Sister Chromatids;Mitotic Anaphase;Mitotic Metaphase and Anaphase;M Phase;Cell Cycle;Resolution of Sister Chromatid Cohesion;ER to Golgi Anterograde Transport;Cell Cycle, Mitotic;Anchoring of the basal body to the plasma membrane;Lissencephaly gene (LIS1) in neuronal migration and development;Intra-Golgi and retrograde Golgi-to-ER traffic;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.375

Intolerance Scores

• loftool: 0.0192
• rvis_EVS: -6.01
• rvis_percentile_EVS: 0.04

Haploinsufficiency Scores

• pHI: 0.468
• hipred: Y
• hipred_score: 0.696
• ghis: 0.676

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.849

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dync1h1
• Phenotype: muscle phenotype; growth/size/body region phenotype; reproductive system 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); 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: dync1h1
• Affected structure: retinal rod cell
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: G2/M transition of mitotic cell cycle;endoplasmic reticulum to Golgi vesicle-mediated transport;microtubule-based movement;mitotic spindle organization;regulation of G2/M transition of mitotic cell cycle;antigen processing and presentation of exogenous peptide antigen via MHC class II;cytoplasmic microtubule organization;positive regulation of intracellular transport;cytoplasmic mRNA processing body assembly;stress granule assembly;neutrophil degranulation;establishment of spindle localization;cell division;regulation of mitotic spindle organization;minus-end-directed vesicle transport along microtubule;regulation of metaphase plate congression;ciliary basal body-plasma membrane docking;positive regulation of cold-induced thermogenesis;positive regulation of spindle assembly
• Cellular component: extracellular region;centrosome;cytosol;cytoplasmic dynein complex;microtubule;membrane;filopodium;dynein complex;azurophil granule lumen;extracellular exosome
• Molecular function: RNA binding;protein binding;ATP binding;ATP-dependent microtubule motor activity, minus-end-directed;dynein light chain binding;dynein intermediate chain binding;dynein light intermediate chain binding