ODAD1

protein-coding

outer dynein arm docking complex subunit 1, the group of Outer dynein arm docking complex subunits

Gene summary

This gene encodes a coiled-coil domain-containing protein that is a component of the outer dynein arm docking complex in cilia cells. Mutations in this gene may cause primary ciliary dyskinesia 20. [provided by RefSeq, May 2013]

Previous symbols:

CCDC114

MANE transcript

NM_001364171.2

Inheritance

AR, AD

ClinVar variants

P:30U:252B:179

Top phenotype

Ciliary dyskinesia, primary, 20

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr19:48,296,457-48,321,971

External References & Databases

Ensembl (ENSG00000105479)

Transcript & Mutation Effects

hg38 • Region Span ~25.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary ciliary dyskinesia 20DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014030

Submitter: ClinGen

*ODAD1*, also known as *CCDC114*, was first reported in relation to Primary Ciliary Dyskinesia in 2013 (PMIDs 23261302 and 23261303). It encodes a coiled-coil domain-containing protein that is an essential component of the outer dynein arm-docking complex required for the correct attachment of the ODA to the microtubule doublet (PMID: 35163670). Reported PCD phenotype in patients with *ODAD1* mutations includes decreased nasal nitric oxide, recurrent respiratory tract infections, neonatal respiratory distress, bronchiectasis, and/or situs abnormalities along with ultrastructural ODA defect (PMIDs 23261302 and 23261303). Milder phenotype has been linked to a partially functioning mutant protein which allowed for assembly of some ODAs and a significant level of ciliary activity (PMID: 35163670). 5 (frameshift and splice site) variants that have been reported in 6 probands carrying biallelic *ODAD1* mutations are included in this curation (PMIDs: 23261302, 23261303 and 35163670). A conserved haplotype is detected to lie in cis with the 853G>A variant, compatible with being a founder mutation (PMID: 23261303). Segregation analysis in multiple Volendam family members confirmed a consistent recessive pattern of inheritance (PMID: 23261303). Lack of infertility among affected family members is suggested to arise from genetic redundancy as CCDC63 could potentially replace CCDC114 function in sperm (PMID: 23261303). Experimental evidence also supports this gene disease relationship. Expression analysis via RT-PCR reveals that *ODAD1* shows high expression in lung and testis (PMID: 23261302). Subcellular localization of ODAD1 protein confirmed its expression along the entire length of human cilia (PMID: 23261303). *ODAD1* mutant cilia showed abnormal ciliary motility comprising large areas of static cilia, with occasionally stiff cilia having a twitching or flickering movement that is slow, and ineffective for mucus transport across the epithelial surface (PMID: 23261303). ODAD1 expression in cultured human bronchial cells paralleled the time course of ciliary differentiation and DNAI1 expression which indicates a crucial role in ciliogenesis (PMID: 23261302). The Chlamydomonas orthologue of *ODAD1* (Oda1; Dcc2) has been shown to be a component of the outer dynein arm docking complex (ODA-DC) that is essential for the assembly of the ODA (PMID: 11907279). In summary, *ODAD1* is definitively associated with autosomal recessive Primary Ciliary Dyskinesia 20. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld overtime. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 17, 2022 (SOP Version 9).

primary ciliary dyskinesia 20DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014030

Submitter: G2P

primary ciliary dyskinesia 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014030

Submitter: Labcorp Genetics (formerly Invitae)

primary ciliary dyskinesiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016575

Submitter: Orphanet

Clinical Genomic Database (CGD)

Ciliary dyskinesia, primary, 20AR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Gastrointestinal; Pulmonary

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Pulmonary

Rationale: Pulmonary and audiologic surveillance may be beneficial to assess respiratory and hearing function and institute early management measures; In order to facilitate mucus clearance, aggressive interventions (eg, chest percussion and oscillatory vest), as well as vaccinations and early and aggressive treatment of respiratory infections may be beneficial, though measures including lobectomy or lung transplantation may be necessary

Refs: 23261302; 23261303

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ODAD1 variants in ClinVar

8 Conditions Cataloged

Primary ciliary dyskinesiaTotal: 544

not providedTotal: 76

Primary ciliary dyskinesia 20Total: 40

not specifiedTotal: 26

ODAD1-related disorderTotal: 15

Adams-Oliver syndrome 5Total: 2

Kartagener syndromeTotal: 1

Fraser syndrome 3Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001364171.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				133 clinvar	3 clinvar	136
missense		2 clinvar	248 clinvar	37 clinvar	6 clinvar	293
nonsense	3 clinvar	3 clinvar				6
start loss						0
frameshift	7 clinvar	3 clinvar	4 clinvar			14
splice donor/acceptor (+/-2bp)	4 clinvar	8 clinvar				12
Total	14	16	252	170	9	461

Highest pathogenic variant AF is 0.00024793256

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001364171.2	RefSeq	NP_001351100.1	14	MANE Select
ENST00000674294.1	Ensembl	ENSP00000501363.1	14	MANE Select
NM_144577.4	RefSeq	NP_653178.3	13	Standard
ENST00000315396.7	Ensembl	ENSP00000318429.7	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cilium movement
outer dynein arm assembly

Molecular Function

protein binding

Cellular Component

cilium
axoneme
outer dynein arm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315396
Coding exons: 13
Length: 25438
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125742
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.480	406	434	0.935	0.0000288	4381
Missense (PolyPhen)		119	144.17	0.8254		1559
Synonymous	1.18	169	190	0.891	0.0000131	1317
Loss of Function	1.71	17	26.5	0.641	0.00000122	302

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000073	0.000070	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable component of the outer dynein arm complex required along the entire axoneme for tethering of outer dynein arms. {ECO:0000305|PubMed:23261302, ECO:0000305|PubMed:23261303}.;
Disease: DISEASE: Ciliary dyskinesia, primary, 20 (CILD20) [MIM:615067]: A disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia. Patients may exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. Unlike other forms of CILD characterized by reduced fertility, patients with CILD20 do not appear to be infertile. {ECO:0000269|PubMed:23261302, ECO:0000269|PubMed:23261303}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.693
RVIS EVS: 1.43
RVIS percentile EVS: 94.99

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.205

Gene Damage Prediction

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