MYO18B

protein-coding

myosin XVIIIB, the group of Myosin heavy chains, class XVIII

Gene summary

The protein encoded by this gene may regulate muscle-specific genes when in the nucleus and may influence intracellular trafficking when in the cytoplasm. The encoded protein functions as a homodimer and may interact with F actin. Mutations in this gene are associated with lung cancer. [provided by RefSeq, Jul 2008]

MANE transcript

NM_032608.7

Inheritance

ClinVar variants

P:157U:1078B:767

Top phenotype

Klippel-Feil syndrome 4, autosomal recessive, with nemaline myopathy and facial dysmorphism

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr22:25,742,144-26,031,045

External References & Databases

Ensembl (ENSG00000133454)

Transcript & Mutation Effects

hg38 • Region Span ~288.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Klippel-Feil anomaly-myopathy-facial dysmorphism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014689

Submitter: Labcorp Genetics (formerly Invitae)

Klippel-Feil anomaly-myopathy-facial dysmorphism syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014689

Submitter: Ambry Genetics

Klippel-Feil anomaly-myopathy-facial dysmorphism syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014689

Submitter: ClinGen

*MYO18B* was first reported in patients with autosomal recessive Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome in 2015 (PMID 25748484). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Numerous pathogenic nonsense and frameshift variants in relation to Klippel-Feil syndrome have been submitted to ClinVar. Nine variants (nonsense, frameshift, splice-site) that have been reported in twelve probands in seven publications (PMIDs: 25748484, 27858739, 30932893. 31195167, 32184166, 32637634, 33179433) and in ClinVar (Variation ID: 3382539) are included in this curation. At least one variant, *MYO18B*:c.6905C>A (p.Ser2302Ter), reported in homozygosity in six affected individuals in the Saudi Arabian population (PMIDs: 25748484, 33179433), is suspected to be a founder variant. An additional report of four individuals harboring biallelic *MYO18B* variants and affected with congenital myopathy, cardiomyopathy, short stature, Klippel-Feil anomaly, and dysmorphisms has been described (Donkervoort et al., 2023 abstract presented at 2023 World Muscle Society Congress). Although heterozygous *MYO18B* missense variants were reported in patients affected by Klippel-Feil syndrome (PMID: 32278351), the overall mechanism for disease is postulated to be homozygous loss of function (PMID: 32184166). Experimental-level genetic evidence supporting this gene-disease relationship includes animal model (PMIDs: 27879346, 28104788), non-human cell model (PMID: 30581023) and mRNA expression studies (PMIDs: 12547197). Also of note, both clinical and functional evidence to date suggest variants in *MYO18B* are associated with congenital myopathy, not nemaline myopathy, although nemaline rods may occur as a secondary consequence of disease. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The *MYO18B*-autosomal recessive Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome gene-disease pair was originally evaluated by the Congenital Myopathies GCEP on June 28, 2021. It was reevaluated on April 28, 2025. As a result of this re-evaluation, the classification increased from Moderate to Definitive with the addition of two variants, experimental evidence from zebrafish and cell models, and application of current version of the gene curation guidelines. This classification was approved by the ClinGen Congenital Myopathies Gene Curation Expert Panel on the meeting date April 28, 2025 (SOP Version 11).

Klippel-Feil anomaly-myopathy-facial dysmorphism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014689

Submitter: Orphanet

Klippel-Feil anomaly-myopathy-facial dysmorphism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014689

Submitter: PanelApp Australia

Klippel-Feil anomaly-myopathy-facial dysmorphism syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014689

Submitter: G2P

Klippel-Feil anomaly-myopathy-facial dysmorphism syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014689

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Klippel-Feil syndrome 4, autosomal recessive, with nemaline myopathy and facial dysmorphismAR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Refs: 25748484

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYO18B variants in ClinVar

13 Conditions Cataloged

not providedTotal: 2114

Inborn genetic diseasesTotal: 464

MYO18B-related disorderTotal: 210

not specifiedTotal: 191

Klippel-Feil anomaly-myopathy-facial dysmorphism syndromeTotal: 159

Limb-girdle muscular dystrophyTotal: 2

Klippel-Feil syndromeTotal: 2

CardiomyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032608.7. 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			8 clinvar	638 clinvar	16 clinvar	662
missense			1062 clinvar	101 clinvar	11 clinvar	1174
nonsense	47 clinvar	21 clinvar	2 clinvar			70
start loss						0
frameshift	37 clinvar	22 clinvar	3 clinvar			62
splice donor/acceptor (+/-2bp)	1 clinvar	29 clinvar	3 clinvar	1 clinvar		34
Total	85	72	1078	740	27	2002

Highest pathogenic variant AF is 0.00014130176

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032608.7	RefSeq	NP_115997.5	42	MANE Select
ENST00000335473.12	Ensembl	ENSP00000334563.8	42	MANE Select
NM_001318245.2	RefSeq	NP_001305174.1	42	Standard
ENST00000407587.6	Ensembl	ENSP00000386096.2	42	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
myo18b	Danio rerio	Structure: fast muscle cell Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

myo18b

Danio rerio

Structure: fast muscle cell

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

vasculogenesis
in utero embryonic development
cardiac muscle fiber development

Molecular Function

motor activity
actin binding
ATP binding

Cellular Component

nucleus
unconventional myosin complex
Z disc
filamentous actin

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000335473
Coding exons: 42
Length: 288897
Individuals with no LoFs: 124535
Homozygous LoFs: 0
Heterozygous LoFs: 245
Defined: 124780
p: 0.000982

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.177	1443	1.46e+3	0.987	0.0000907	16483
Missense (PolyPhen)		446	457.6	0.97465		5347
Synonymous	-0.201	603	597	1.01	0.0000381	5053
Loss of Function	4.19	70	119	0.586	0.00000609	1358

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0016	0.0015	notable
Latino/Admixed American	0.0017	0.0017	notable
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00090	0.00089	rare
Finnish	0.000096	0.000093	rare
European (Non-Finnish)	0.00087	0.00086	rare
South Asian	0.0013	0.0012	notable
Other	0.0015	0.0015	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in intracellular trafficking of the muscle cell when in the cytoplasm, whereas entering the nucleus, may be involved in the regulation of muscle specific genes. May play a role in the control of tumor development and progression; restored MYO18B expression in lung cancer cells suppresses anchorage-independent growth.;
Disease: DISEASE: Klippel-Feil syndrome 4, autosomal recessive, with nemaline myopathy and facial dysmorphism (KFS4) [MIM:616549]: A form of Klippel-Feil syndrome, a skeletal disorder characterized by congenital fusion of cervical vertebrae. It is due to a failure in the normal segmentation of vertebrae during the early weeks of fetal development. The clinical triad consists of short neck, low posterior hairline, and limited neck movement. KFS4 features additionally include myopathy, mild short stature, microcephaly, and distinctive facies. {ECO:0000269|PubMed:25748484}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.0545
RVIS EVS: 1.21
RVIS percentile EVS: 93.02

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.125

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High