MYO6

Chr 6ADAR

myosin VI

Also known as: DFNA22, DFNB37

NCBI Gene: 4646 ENSG00000196586 UniProt: Q9UM54 OMIM: 600970

MYO6 encodes an unconventional myosin motor protein that moves toward the minus end of actin filaments and functions in intracellular vesicle transport, endocytosis, autophagy, and maintenance of inner ear hair cell structural integrity. Mutations cause non-syndromic hearing loss with both autosomal dominant and autosomal recessive inheritance patterns, with some dominant cases also presenting with hypertrophic cardiomyopathy. The gene is highly constrained against loss-of-function variants (LOEUF 0.419), indicating that such variants are likely pathogenic.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.423 OMIM phenotypes

Clinical Summary— MYO6

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

114 unique Pathogenic / Likely Pathogenic· 485 VUS of 980 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MYO6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.000

Z-score 5.92

OE 0.30 (0.22–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.39Z-score

OE missense 0.85 (0.79–0.91)

586 obs / 688.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.22–0.42)

0≤0.351.4

Missense OE?0.85 (0.79–0.91)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 25 / 83.4Missense obs/exp: 586 / 688.6Syn Z: 0.59

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateMYO6-related nonsyndromic genetic hearing loss with left ventricular hypertrophyOTHERAR

moderateMYO6-related nonsyndromic genetic hearing loss with left ventricular hypertrophyOTHERAD

definitiveMYO6-related nonsyndromic genetic hearing lossOTHERAR

definitiveMYO6-related nonsyndromic genetic hearing lossOTHERAD

This gene — mechanism propensity

0.77top 25%

GOF

0.6736th %ile

LOF

0.2677th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 84% of P/LP variants are LoF · LOEUF 0.42

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFThus, our study indicated that MYO6 haploinsufficiency affected the detection of sounds in mice, and we suggest that +/- mice with Myo6 null alleles are useful animal models for gene therapy and drug treatment in patients with progressive hearing loss due to MYO6 haploinsufficiency.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 34619316 ↗

ClinVar Variant Classifications

980 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59

Likely Pathogenic55

VUS485

Likely Benign182

Benign100

Conflicting72

Pathogenic

Likely Pathogenic

485

VUS

182

Likely Benign

100

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	53	1	5	0	59
Likely Pathogenic	43	8	4	0	55
VUS	10	383	85	7	485
Likely Benign	0	5	117	60	182
Benign	0	3	96	1	100
Conflicting	—				72
Total	106	400	307	68	953

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap MYO6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →