GeneBe

MYO6

protein-coding

myosin VI, the group of Myosin heavy chains, class VI

Gene summary

This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

Previous symbols:
  • DFNA22
  • DFNB37

MANE transcript

NM_004999.4

Inheritance

AR, AD, SD

ClinVar variants

P:131U:458B:101

Top phenotype

Deafness, autosomal dominant 22; Deafness, autosomal recessive 37

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr6:75,749,201-75,919,537

External References & Databases

Ensembl (ENSG00000196586)NCBI Gene (4646)OMIM (600970)HGNC:7605GenCCUniProt (Q9UM54)AlphaFoldClinVar (MYO6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~170.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 37STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011912

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing loss 22STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011660

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: G2P

progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016424

Submitter: Orphanet

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The MYO6 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/4/16. This association was made using case-level data only. At least 7 missense, nonsense and frameshift variants have been reported in humans. Loss-of-function variants cause autosomal dominant progressive hearing loss with variable age of onset (childhood – 30s). Hypomorphic missense variants likely are only hearing loss-causing when in trans with a second variant. A family reported in Brownstein et al. 2014 (24105371) had in-frame exon 10 deletion and dominant, progressive hearing loss, with one homozygote with profound congenital HL. This supports MYO6 as dose-dependent. MYO6 was first associated with this disease in humans as early as 2001 (Melchionda et al.). Association is seen in at least 8 probands in 4 publications (11468689, 25999546, 25227905, 18348273). Variants in this gene segregated with disease in >44 additional family members. Three mouse models exist for MYO6, one of which a heterozygote has mild HL. In summary, MYO6 is definitively associated with autosomal dominant nonsyndromic hearing loss. Based on literature review, semi-dominance is likely, in which biallelic variants cause more severe hearing loss. No distinction in mechanism between AD and AR disease exists for this gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 2/20/18.

nonsyndromic genetic hearing lossSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0019497

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 22DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011660

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 37MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011912

Submitter: Ambry Genetics

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: G2P

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 22; Deafness, autosomal recessive 37AD/AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Deafness, autosomal dominant 22 may involve hypertrophic cardiomyopathy, and awareness may enable early identification and management of cardiac manifestations; In Deafness, autosomal recessive 37, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: One kindred has been described also segregating hypertrophic cardiomyopathy with the MYO6 variant, but the overall evidence appears mixed as relates to cardiac findings

Refs: 11468689; 12687499; 15060111; 18212818; 18348273; 19893302; 28000701; 29044474; 29224747Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYO6 variants in ClinVar

20 Conditions Cataloged
not providedTotal: 617
not specifiedTotal: 138
Autosomal dominant nonsyndromic hearing loss 22Total: 127
Inborn genetic diseasesTotal: 113
MYO6-related disorderTotal: 108
Autosomal recessive nonsyndromic hearing loss 37Total: 103
Rare genetic deafnessTotal: 12
Hearing impairmentTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004999.4. 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.

EffectPLPVUSLBBSum
synonymous
7
clinvar
77
clinvar
4
clinvar
 88
missense
1
clinvar
11
clinvar
430
clinvar
11
clinvar
9
clinvar
 462
nonsense
17
clinvar
22
clinvar
2
clinvar
 41
start loss
0
frameshift
28
clinvar
22
clinvar
4
clinvar
 54
splice donor/acceptor (+/-2bp)
9
clinvar
21
clinvar
15
clinvar
 45
Total55764588813690

Highest pathogenic variant AF is 0.0035191583

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004999.4RefSeqNP_004990.334MANE Select
ENST00000369977.8EnsemblENSP00000358994.334MANE Select
NM_001300899.2RefSeqNP_001287828.132Standard
NM_001368136.1RefSeqNP_001355065.131Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
myo6aDanio rerio

Structure: angioblastic mesenchymal cell

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • VEGFA-VEGFR2 Signaling Pathway
  • Vesicle-mediated transport
  • Membrane Trafficking
  • Neuronal System
  • EGFR1

Biological Process

  • intracellular protein transport
  • endocytosis
  • sensory perception of sound
  • actin filament-based movement
  • DNA damage response, signal transduction by p53 class mediator

Molecular Function

  • motor activity
  • actin binding
  • protein binding
  • calmodulin binding
  • ATP binding

Cellular Component

  • ruffle
  • nucleus
  • nucleoplasm
  • cytoplasm
  • lysosomal membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000369977
Coding exons
34
Length
170346
Individuals with no LoFs
125680
Homozygous LoFs
0
Heterozygous LoFs
68
Defined
125748
p
0.000270
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.395866890.8510.00003788555
Missense (PolyPhen)8594.3020.901361092
Synonymous0.5932192300.9500.00001182251
Loss of Function5.922583.40.3000.00000480971

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000310.00031rare
Latino/Admixed American0.000410.00040rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000110.00011rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.000280.00028rare
South Asian0.000330.00033rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Myosin 6 is a reverse-direction motor protein that moves towards the minus-end of actin filaments. Has slow rate of actin-activated ADP release due to weak ATP binding. Functions in a variety of intracellular processes such as vesicular membrane trafficking and cell migration. Required for the structural integrity of the Golgi apparatus via the p53-dependent pro-survival pathway. Appears to be involved in a very early step of clathrin-mediated endocytosis in polarized epithelial cells. May act as a regulator of F-actin dynamics. May play a role in transporting DAB2 from the plasma membrane to specific cellular targets. Required for structural integrity of inner ear hair cells (By similarity). {ECO:0000250, ECO:0000269|PubMed:10519557, ECO:0000269|PubMed:11447109, ECO:0000269|PubMed:16507995, ECO:0000269|PubMed:16949370}.;
Disease
DISEASE: Deafness, autosomal dominant, 22 (DFNA22) [MIM:606346]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA22 is progressive and postlingual, with onset during childhood. By the age of approximately 50 years, affected individuals invariably have profound sensorineural deafness. {ECO:0000269|PubMed:11468689}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 37 (DFNB37) [MIM:607821]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:12687499}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant 22, with hypertrophic cardiomyopathy (DFNHCM) [MIM:606346]: An autosomal dominant sensorineural deafness associated with hypertrophic cardiomyopathy. {ECO:0000269|PubMed:15060111}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.319

Intolerance Scores

LoFtool
0.179
RVIS EVS
-0.37
RVIS percentile EVS
28.26

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.301

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.